Insulin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

NSULIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J AMES N. P AR...

Author: Health Publica Icon Health Publications

20 downloads 920 Views 4MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

NSULIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Insulin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83943-3 1. Insulin-Popular works. I. Title.

iii

Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on insulin. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

v

About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

vi

About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON INSULIN ..................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Insulin......................................................................................... 19 E-Journals: PubMed Central ....................................................................................................... 80 The National Library of Medicine: PubMed .............................................................................. 108 CHAPTER 2. NUTRITION AND INSULIN ......................................................................................... 157 Overview.................................................................................................................................... 157 Finding Nutrition Studies on Insulin........................................................................................ 157 Federal Resources on Nutrition ................................................................................................. 166 Additional Web Resources ......................................................................................................... 167 CHAPTER 3. ALTERNATIVE MEDICINE AND INSULIN ................................................................... 171 Overview.................................................................................................................................... 171 National Center for Complementary and Alternative Medicine................................................ 171 Additional Web Resources ......................................................................................................... 187 General References ..................................................................................................................... 198 CHAPTER 4. DISSERTATIONS ON INSULIN ..................................................................................... 199 Overview.................................................................................................................................... 199 Dissertations on Insulin ............................................................................................................ 199 Keeping Current ........................................................................................................................ 214 CHAPTER 5. CLINICAL TRIALS AND INSULIN ............................................................................... 215 Overview.................................................................................................................................... 215 Recent Trials on Insulin............................................................................................................. 215 Keeping Current on Clinical Trials ........................................................................................... 230 CHAPTER 6. PATENTS ON INSULIN ............................................................................................... 233 Overview.................................................................................................................................... 233 Patents on Insulin...................................................................................................................... 233 Patent Applications on Insulin .................................................................................................. 262 Keeping Current ........................................................................................................................ 298 CHAPTER 7. BOOKS ON INSULIN ................................................................................................... 299 Overview.................................................................................................................................... 299 Book Summaries: Federal Agencies............................................................................................ 299 Book Summaries: Online Booksellers......................................................................................... 304 The National Library of Medicine Book Index ........................................................................... 311 Chapters on Insulin.................................................................................................................... 312 Directories.................................................................................................................................. 324 CHAPTER 8. MULTIMEDIA ON INSULIN ........................................................................................ 325 Overview.................................................................................................................................... 325 Video Recordings ....................................................................................................................... 325 Audio Recordings....................................................................................................................... 327 Bibliography: Multimedia on Insulin ........................................................................................ 328 CHAPTER 9. PERIODICALS AND NEWS ON INSULIN ..................................................................... 331 Overview.................................................................................................................................... 331 News Services and Press Releases.............................................................................................. 331 Newsletters on Insulin............................................................................................................... 335 Newsletter Articles .................................................................................................................... 335 Academic Periodicals covering Insulin ...................................................................................... 337 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 339 Overview.................................................................................................................................... 339 U.S. Pharmacopeia..................................................................................................................... 339

viii Contents

Commercial Databases ............................................................................................................... 341 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 345 Overview.................................................................................................................................... 345 NIH Guidelines.......................................................................................................................... 345 NIH Databases........................................................................................................................... 347 Other Commercial Databases..................................................................................................... 350 The Genome Project and Insulin................................................................................................ 350 APPENDIX B. PATIENT RESOURCES ............................................................................................... 357 Overview.................................................................................................................................... 357 Patient Guideline Sources.......................................................................................................... 357 Finding Associations.................................................................................................................. 379 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 383 Overview.................................................................................................................................... 383 Preparation................................................................................................................................. 383 Finding a Local Medical Library................................................................................................ 383 Medical Libraries in the U.S. and Canada ................................................................................. 383 ONLINE GLOSSARIES................................................................................................................ 389 Online Dictionary Directories ................................................................................................... 391 INSULIN DICTIONARY.............................................................................................................. 393 INDEX .............................................................................................................................................. 491

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with insulin is indexed in search engines, such as www.google.com or others, a nonsystematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about insulin, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to insulin, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on insulin. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to insulin, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on insulin. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON INSULIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on insulin.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and insulin, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “insulin” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Exercising with an Insulin Pump Source: Diabetes Self-Management. 19(1): 63-70. January-February 2002. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Website: www.diabetes-self-mgmt.com. Summary: Active people who use insulin need to make frequent adjustments in their diabetes regimen to maintain blood glucose in target range, especially when doing higher intensity or longer duration exercise. But the effort can pay off in improved blood glucose control, reduced nighttime hypoglycemia (low blood glucose levels), improved cardiovascular fitness, and weight loss. This article describes how insulin pump therapy may be a good option for managing exercise and insulin needs efficiently. Insulin pumps given both basal insulin doses (background insulin delivered every few minutes

4

Insulin

in small increments to cover the body's general need for insulin) and boluses (larger doses given to cover meals and snacks or to lower elevated blood glucose at any time). All insulin pumps currently on the market delivery insulin subcutaneously (under the skin) in the abdomen, buttocks, legs, or upper arms, either through a needle or through a plastic infusion catheter. Pumps users replace the needle or catheter infusion set every two to three days with a new set at a new site. The article concludes with a list of basic guidelines to help users maintain good blood glucose control: understand the nature of the exercise activity, predict the blood glucose response and make regimen changes, learn from the past, prevent hypoglycemia, and expect a training response. The article includes a chart of sample basal profiles and a list of resources for finding information about insulin pumps. 1 table. •

Glycemic and Insulinemic Response of Subjects with Type 2 Diabetes After Consumption of Three Energy Bars Source: Journal of the American Dietetic Association. 102(8): 1139-1142. August 2002. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Adequate control of postprandial (after a meal) blood glucose levels is an important component of overall blood glucose management. Diabetes snack bars designed to slow the rate of carbohydrate digestion and absorption may be useful in lowering postprandial blood glucose levels and potentially improving glycemic control. This article reports on a study that evaluated the acute effects of ingestion of equivalent quantities of resistant starch and fully digestible starch, as part of a snack bar, on postprandial blood glucose and insulin levels in subjects with type 2 diabetes. The study included 7 men and 3 women with type 2 diabetes controlled by medical nutrition therapy (MNT) alone. Results showed that the mean peak blood glucose level at 60 minutes for the resistant starch bar was significantly lower than that of the traditional energy bar and the candy bar. The authors conclude with strategies for the practical application of the knowledge gained in this study. 1 figure. 1 table. 32 references.

•

Is Insulin Sensitivity a Causal Intermediate in the Relationship Between Alcohol Consumption and carotid Atherosclerosis?: The Insulin Resistance and Atherosclerosis Study Source: Diabetes Care. 25(8): 1425=1431. August 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: An association has been demonstrated between alcohol consumption and atherosclerosis. Insulin resistance, also a risk factor for atherosclerosis, has been shown to have a similar association with alcohol intake. This raises the question of whether insulin sensitivity is a causal intermediate in the alcohol-atherosclerosis relationship. This article reports on the Insulin Resistance Atherosclerosis Study, a multicenter cohort study designed to investigate relationships among insulin sensitivity, risk factors for cardiovascular disease, and carotid artery atherosclerosis. A J-shaped association was observed between alcohol consumption and common carotid artery intimal medial thickness. The protective aspect of the alcohol-atherosclerosis relationship was attenuated by 25 percent after the adjustment for insulin sensitivity. However, an interaction was observed between alcohol consumption and glucose tolerance (GT) status. In comparison with never-drinkers, all levels of alcohol consumption were associated with less atherosclerosis in participants with normal GT status. Participants

Studies

5

with impaired GT status (but not diabetes) demonstrated a J-shaped alcoholatherosclerosis association. All levels of alcohol consumption were association with more atherosclerosis in participants with diabetes. These findings contrast with previous reports and do not support current recommendations regarding moderate alcohol consumption in people with diabetes. The authors call for more research to clarify this issue. 2 figures. 1 table. 43 references. •

Continuous Subcutaneous Insulin Infusion at 25 Years: Evidence Base for the Expanding use of Insulin Pump Therapy in Type 1 Diabetes Source: Diabetes Care. 25(3): 593-598. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Continuous subcutaneous insulin infusion (CSII) is used in selected type 1 diabetes subjects to achieve strict blood glucose control. This article reviews the evidence base that justifies the present increase in the use of CSII, including effectiveness compared with modern intensified insulin injection regimens and concern about possible complications. Review of controlled trials shows that, in most patients, mean blood glucose concentrations and glycated hemoglobin percentages are either slightly lower or similar on CSII versus multiple insulin injections. However, hypoglycemia (low blood glucose) is markedly less frequent than during intensive injection therapy. Ketoacidosis occurs at the same rate. Nocturnal glycemic control is improved with insulin pumps, and automatic basal rate changes help to minimize a prebreakfast blood glucose increase (the dawn phenomenon) often seen with injection therapy. Patients with brittle diabetes characterized by recurrent ketoacidosis are often not improved by CSII, although there may be exceptions. The authors argue that explicit clinical indications for CSII are helpful; they suggest the principal indications for health service or health insurance-funded CSII should include frequent, unpredictable hypoglycemia or a marked dawn phenomenon, which persist after attempts to improve control with intensive insulin injection regimens. In any circumstances, candidates for CSII must be motivated, willing and able to undertake pump therapy, and adequately psychologically stable. Some diabetic patients with well defined clinical problems are likely to benefit substantially from CSII and should not be denied a trial of the treatment. 72 references.

•

Effects of Diets Enriched in Saturated (Palmitic), Monounsaturated (Oleic), or trans (Elaidic) Fatty Acids on Insulin Sensitivity and Substrate Oxidation in Healthy Adults Source: Diabetes Care. 25(8): 1283-1288. August 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Diets high in total and saturated fat are associated with insulin resistance. This article reports on a study that examined the effects of feeding monounsaturated, saturated, and trans fatty acids on insulin action in healthy adults. The randomized, double-blind, crossover study was conducted comparing three controlled 4 week diets (57 percent carbohydrate, 28 percent fat, and 15 percent protein) enriched with different fatty acids in 25 healthy men and women. After each diet period, insulin pulsatile secretion, insulin sensitivity index by the minimal model method, serum lipids, and fat oxidation by indirect calorimetry were measured. Insulin sensitivity decreased by 24 percent on the saturated fat versus the monounsaturated fat diet in overweight subjects

6

Insulin

but was unchanged in lean subjects (not significant). Insulin secretion was unaffected by diet, whereas total and HDL cholesterol increased significantly on the saturated fat diet. Subjects oxidized the least fat on the monounsaturated fat diet and the most fat on the trans fatty acid diet. The authors conclude that dietary fatty acid composition significantly influenced fat oxidation but did not have an impact on insulin sensitivity or secretion in lean individuals. Overweight individuals were more susceptible to developing insulin resistance on high-saturated fat diets. 3 tables. 32 references. •

Effects of Moderate Alcohol Intake on Fasting Insulin and Glucose Concentrations and Insulin Sensitivity in Postmenopausal Women: A Randomized Control Trial Source: JAMA. Journal of the American Medical Association. 287(19): 2559-2562. May 15, 2002. Summary: Epidemiological data demonstrate that moderate alcohol intake is associated with improved insulin sensitivity in nondiabetic individuals. No controlled-diet studies have addressed the effects of daily moderate alcohol consumption on fasting insulin and glucose concentrations and insulin sensitivity. This article reports on a study undertaken to determine whether daily consumption of low to moderate amounts of alcohol influences fasting insulin and glucose concentrations and insulin sensitivity in nondiabetic postmenopausal women. The randomized controlled crossover trial included 63 healthy postmenopausal women. Results showed that consumption of 30 grams per day of alcohol compared with 0 grams per day reduced fasting insulin concentration by 19.2 percent and triglyceride concentration by 10.3 percent, and increased insulin sensitivity by 7.2 percent. Normal weight, overweight, and obese individuals responded in similar ways. Fasting glucose concentrations were not different across treatments. The authors conclude that consumption of 30 grams of alcohol (2 drinks per day) has beneficial effects on insulin and triglyceride concentrations and insulin sensitivity in nondiabetic postmenopausal women. 1 figure. 2 tables. 35 references.

•

Factor Analysis of Metabolic Syndrome Using Directly Measured Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study Source: Diabetes. 51(7): 2642-2647. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of metabolic syndrome, which is characterized by physiological complexity and strong statistically intercorrelation among its key variables. This article reports on a study that investigated, using factor analysis, the clustering of physiologic variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). This study includes information on the directly measured insulin sensitivity index from intravenous glucose tolerance testing among African-American, Hispanic, and non-Hispanic white subjects aged 40 to 69 years at various stages of glucose tolerance. Factor analysis identified two underlying factors among a group of metabolic syndrome variables in this dataset. Analyses using surrogate measures of insulin resistance suggested that these variables provide adequate information to explore the underlying intercorrelational structure of metabolic syndrome. Additional clarification of the physiologic characteristics of metabolic syndrome is required as individuals with this condition are increasingly being

Studies

7

considered candidates for behavioral and pharmacologic (drug) intervention. 6 tables. 38 references. •

Business of Insulin Pumps in Diabetes Care: Clinical and Economic Considerations Source: Clinical Diabetes. 20(4): 214-216. October 1, 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Insulin pumps provide one of three commercially available technologies for insulin delivery. This article considers the clinical and economic considerations of the use of insulin pumps in diabetes care. The authors suggest that pen-injected insulin therapy and continuous subcutaneous insulin infusion (CSII) therapy are both associated with higher costs than is syringe-injected insulin therapy. When equipment costs are added to the cost of supplies, CSII is only slightly more expensive than peninjected insulin therapy on an annual basis. Data in favor of these newer forms of insulin administration are most substantial in relation to patient acceptance, flexibility of injection regimen, and reduction in omissions of scheduled doses. In contract to widespread perceptions of CSII, which are encouraged by the marketing efforts of pump manufacturers, there is no clear evidence that CSII therapy enhances glycemic control compared to other forms of insulin therapy. CSII does, however, appear to reduce the risks of hypoglycemic for the same level of control and, as with pens, may help more patients accept intensive insulin therapy. Because CSII lends itself to intensive management of hyperglycemia, positive public perceptions regarding insulin pumps may aid in the advocacy of strict glycemic control for people with insulin-requiring diabetes. 2 tables. 15 references.

•

Basal-Bolus Insulin Therapy Source: Practical Diabetology. 21(1): 33-36. March 2002. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: Insulin regimens continue to improve in their ability to mimic the natural actions of the pancreas. This article reviews the use of basal-bolus insulin therapy, a type of insulin regimen that is intended to provide both long-acting, low basal (body) levels of insulin and short-acting boluses for mealtime increases in glucose. The author uses a case study to discuss the implementation and benefits of basal-bolus therapy with insulin glargine and a short-acting insulin. Glargine offers many characteristics of an ideal basal insulin: the pharmacodynamics of this drug allow for a slower absorption rate, resulting in a relatively stable and constant concentration over 24 hours, with no pronounced peaks. The author concludes that the combination of insulin glargine as the basal insulin and insulin lispro as the preprandial (before a meal) insulin in a basalbolus regimen has many advantages. The convenience of a once-daily injection of a long-acting insulin and the flexibility in scheduling meals and activities are the most obvious advantages. 2 references.

•

Insulin Resistance, the Metabolic Syndrome, and Risk of Incident Cardiovascular Disease in Nondiabetic American Indians Source: Diabetes Care. 26(3): 861-867. March 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org.

8

Insulin

Summary: Insulin resistance (IR) and the metabolic syndrome (MS) are associated with type 2 diabetes and adverse cardiovascular disease (CVD) risk factor profiles. Whether IR and MS predict CVD independently of diabetes and other CVD risk factors is not known. This article reports on a study that examines whether IR or presence of MR are independently associated with CVD in nondiabetic American Indians (AI). The authors examined 2,283 nondiabetic AI who were free of CVD at the baseline examination of the Strong Heart Study (SHS). CVD risk factors were measured, IR was quantified using the homeostasis model assessment (HOMA), and MS was assessed for each participant. Incident (new) CVD and diabetes were ascertained during follow up. MS was present in 798 individuals (35 percent), and 181 participants (7.9 percent) developed CVD over 7.6 years (plus or minus 1.8 years) of follow up. Age, body mass index (BMI), waist circumference, and triglyceride levels increased and HDL cholesterol decreased across tertiles of HOMA-IR. Risk of diabetes increased as a function of baseline HOMA-IR and MS. In analyses adjusted for CVD risk factors, risk of CVD did not increase either as a function of baseline HOMA-IR or MS, but individual CVD risk factors predicted subsequent CVD. 2 figures. 4 tables. 35 references. •

Business of Insulin: A Relationship Between Innovation and Economics Source: Clinical Diabetes. 21(1): 40-42. October 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Insulin, as a commercial product is undergoing a substantial metamorphosis from a commodity item to a potential growth vehicle for its manufacturers. This article explores the business aspects of insulin, focusing on the relationship between innovation and economics in this area. The author recognizes an acceleration in the rate of change with the introduction of a growing number of insulin analogs and new insulin injection devices. Although this innovation has, of course, been presented as improved medical therapy, the business aspects of the insulin market suggest that the economic rewards are important drivers of these developments. The author considers innovations in insulin since 1980, innovations in insulin therapy, documentation of the efficacy of these newer insulin products, the pricing of insulin, growth of the insulin market, and clinical and economic decisions about insulin therapy. 2 tables. 16 references.

•

Administration of Neutral Protamine Hagedorn Insulin at Bedtime Versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control Source: Annals of Internal Medicine. 136(7): 547-549. April 2, 2002. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: Intensive insulin treatment of type 1 diabetes mellitus increases the risk for nocturnal hypoglycemia (low levels of blood glucose overnight). This article reports on a study undertaken to demonstrate that splitting the evening insulin regimen reduces the risk for nocturnal hypoglycemia in the intensive treatment of people with type 1 diabetes mellitus (n = 22). Each patient was randomly assigned to one of the two insulin regimens for 4 months and then switched to the other regimen for another 4 months. The treatment regimens were: mixed treatment, i.e., a mixture of human regular and neutral protamine Hagedorn (NPH) insulin administered before dinner; and split treatment, i.e., human regular insulin administered at dinner and NPH insulin

Studies

9

administered at bedtime. During the split regimen treatment period, patients had fewer episodes of nocturnal hypoglycemia, a lower fasting blood glucose level, less variable fasting blood glucose levels, and lower hemoglobin A1c values (a measure of blood glucose over time) than during the mixed regimen. 5 figures. 2 tables. 45 references. •

Morning Hyperglycemic Excursions: a Constant Failure in the Metabolic Control of Non-Insulin-Using Patients with Type 2 Diabetes Source: Diabetes Care. 25(4): 737-741. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: It has been observed in individuals with diabetes that blood glucose concentrations increased during the morning period and remained elevated over a time interval from breakfast to lunch, whereas progressive improvements in blood glucose were observed in more than two thirds of the patients during the second part of the daytime (diurnal). This article reports on research undertaken to determine if one or several hyperglycemia excursions exist that can contribute to general failures in the glycemic control of patients with type 2 diabetes. In 200 non insulin using patients with type 2 diabetes, daytime plasma glucose and insulin profiles were studied. Plasma glucose (blood sugar) concentrations were measured after an overnight fast (at 8:00 A.M. immediately before breakfast), during the postprandial period (at 11:00 A.M. and 2:00 P.M.), and during the postabsorptive period (at 5:00 P.M., extended postlunch time). In the population considered as a whole, prelunch glucose concentrations were found to be significantly increased when compared with those observed at 8:00 A.M., at 2:00 P.M., and at 5:00 P.M. Similar significant excursions in prelunch glucose were observed within subsets of patients selected from the following criteria: body weight, HbA1c, categories of treatment, and residual beta cell function. The relative contributions of postprandial (after a meal) and fasting glucose to the total glucose increment were found to be similar. The authors conclude that high plasma glucose excursions over morning periods seem to be a permanent failure in non insulin using patients with type 2 diabetes, whatever the clinical, biological, therapeutic, and pathophysiological status. Midmorning glucose testing should be recommended for detecting such abnormalities and for correcting them with appropriate therapies. 1 figure. 1 table. 25 references.

•

Effects of Insulin in Relatives of Patients With Type I Diabetes Mellitus Source: New England Journal of Medicine. 346(22): 1685-1691b. May 30, 2002. Contact: Available from New England Journal of Medicine. 860 Winter Street, Waltham, MA 02451-1413. (781) 893-3800. Website: www.nejm.org. Summary: It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes. This article reports on a randomized, controlled, nonblinded clinical trial in which the authors screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet cell antibodies. After analysis and patient selection, 372 relatives were shown to have projected five year risk of more than 50 percent; 339 of these (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low dose subcutaneous ultralente insulin, plus annual four day continuous intravenous infusions of insulin. Median follow up was 3.7 years. Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in

10

Insulin

the observation group. Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal baseline glucose tolerance than among those with normal baseline glucose tolerance. The authors conclude that in persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes. 2 figures. 2 tables. 31 references. •

Amylin Replacement with Pramlintide in Type 1 and Type 2 Diabetes: A Physiological Approach to Overcome Barriers with Insulin Therapy Source: Clinical Diabetes. 20(3): 137-144. Summer 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Many insulin-treated patients with diabetes still fail to achieve optimal glycemic (blood glucose) control and continue to experience problems with hypoglycemia (low blood glucose levels), weight gain, and postprandial (after a meal) hyperglycemia (high blood glucose levels). Adjunctive therapy with pramlintide, a synthetic analog of the human amylin hormone, facilitates a significant improvement of postprandial and overall glycemic control in patients with either type 1 or type 2 diabetes, without an increased risk of hypoglycemia or weight gain. This article reviews the indications for pramlintide and the research that supports its use. For patients with type 1 diabetes, pramlintide represents the first agent in 80 years that has been shown to improve long-term glycemic control above and beyond insulin. For insulin-treated patients with type 2 diabetes, who have typically advanced to a stage where they have exhausted other therapeutic options, pramlintide may become an important addition to the therapeutic armamentarium, especially with its beneficial effects on postprandial glucose control and body weight. 5 figures. 59 references.

•

Errors of Insulin Commission? Source: Clinical Diabetes. 20(4): 221-222. October 1, 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Millions of people take insulin injections several times a day, and with the advent of new insulin analogs and premixed insulin combinations, the potential for errors has increased. This article reviews some of the more common types of insulin errors. Errors discussed include mistaking dosages of different insulins, identifying insulins by their appearance, drawing up inaccurate doses, confusing various premixed products, inappropriately handling insulins, and omitting insulin during illness. The authors offer some hints for ensuring the safety of patients who use insulin. The authors conclude that patients educated in their own diabetes care are the best insurance that mistakes are few and far between and that any mistakes that do occur are less likely to be severe. Referring patients to a certified diabetes educator who can teach them the basics of insulin therapy and administration and offer practical tips for preventing errors can be a smart investment for patients, their family, and their care providers. 1 reference.

•

Insulin Strategies for Primary Care Providers Source: Clinical Diabetes. 20(1): 11-17. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org.

Studies

11

Summary: Primary care providers care for more than 75 percent of the people who have diabetes. This article reviews insulin therapy, focusing on the recent introduction of two new insulin analogs. The authors stress that education about insulin physiology and the use of insulin in patients with diabetes should enable primary care providers to come closer to physiological insulin replacement and return blood glucose (sugar) levels to near-normal concentrations. The authors discuss the currently available types of insulins and the replacement of insulin in a physiological manner for patients with type 1 or type 2 diabetes. The authors provide examples of patients for whom insulin dosages changed over time. Utilizing an insulin algorithm (a decision making chart) and carbohydrate counting not only educates patients about their diabetes but further improves their glycemic control and gives them added control over their diabetes and lifestyle. Insulin pens and insulin pumps provide further diversity for insulin delivery. The authors conclude that no matter what the insulin regimen or means of insulin administration, successful diabetes management requires frequent self-monitoring of blood glucose (SMBG). 33 references. •

New Insulin Therapies for the Management of Diabetes Mellitus Source: Practical Diabetology. 21(1): 14-20. March 2002. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensified insulin treatment in patients with type 1 diabetes reduces the incidence and progression of microvascular complications. These results were echoed by the United Kingdom Prospective Diabetes Study (UKPDS), which confirmed that tight blood glucose control also decreases the risk of microvascular complications in patients with type 2 diabetes. This article explores the use of new insulin preparations, both shortacting and long-acting, which, when combined, are better able to mimic the normal basal (body) and bolus insulin secretion of the normal pancreas, with more consistent absorption. The authors discuss short-acting insulin analogs (lispro or Humalog and aspart or NovoLog), long-acting insulin analogs (notably insulin glargine), premixed insulins, insulin pens, and inhaled insulin systems currently under development. The authors note that these rapid acting analogs make it possible to improve glycemic control without an increase in hypoglycemic events. Glargine, which provides 24 hour basal, peakless insulin, has also minimized hypoglycemic events. These analogs allow physicians to individualize treatments to specific patient characteristics and to achieve further improvements in glycemic control. 2 figures. 1 table. 4 references.

•

Intensive Lifestyle Changes are Necessary to Improve Insulin Sensitivity: A Randomized Controlled Trial Source: Diabetes Care. 25(3): 445-452. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The extent to which lifestyle must be altered to improve insulin sensitivity has not been established. This study compares the effect on insulin sensitivity of current dietary and exercise recommendations with a more intensive intervention in normoglycemic insulin-resistant individuals. The study included 79 normoglycemic (normal levels of blood glucose) insulin-resistant men and women who were randomized to either a control group or one of the two combined dietary and exercise programs. Only the intensive group showed a significant improvement in insulin

12

Insulin

sensitivity (23 percent increase versus 9 percent increase in the modest group). This was associated with a significant improvement in aerobic fitness (11 percent increase in the intensive group, versus 1 percent in the modest group) and a greater fiber intake, but no difference in reported total or saturated dietary fat. Current clinical dietary and exercise recommendations, even when vigorously implemented, did not significantly improve insulin sensitivity; however, a more intensive program did. The authors conclude that improved aerobic fitness appeared to be the major difference between the two intervention groups, although weight loss and diet composition may have also played an important role in determining insulin sensitivity. 1 figure. 3 tables. 25 references. •

Insulin Administration Source: Diabetes Care. 25(Supplement 1): S112-115. January 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The injection of insulin is essential for the management of patients with type 1 diabetes and may be needed by patients with type 2 diabetes for intermittent or continuous glycemic control. This article presents the American Diabetes Association position statement on insulin administration. The statement addresses issues regarding the use of conventional insulin administration (i.e., via syringe or pen with needle and cartridge) in the self care of the individual with diabetes. Topics include the different types and species of insulin, storage of insulin, mixing insulin, syringes, disposal of needles, needle reuse, syringe alternatives, injection techniques, dose preparation, injection procedures, injection site, patient management issues, dosing, self-monitoring of blood glucose (SMBG), and hypoglycemia. The article concludes that the effective use of insulin to obtain the best metabolic control requires an understanding of the duration of action of the various types of insulin and the relationship of blood glucose levels to exercise, food intake, intercurrent illness, certain medications, and stress; SMBG; and learning to adjust insulin dosage to achieve the individualized target goals. 2 references.

•

Do Sensor Glucose Levels Accurately Predict Plasma Glucose Concentrations During Hypoglycemia and Hyperinsulinemia? Source: Diabetes Care. 25(5): 889-893. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three of more fingerstick glucose levels daily. This article reports on a study undertaken to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance. To achieve this, the authors used microdialysis to provide a means to measure changes in interstitial glucose levels directly. Results showed that although hyperinsulinemia (high levels of insulin in the blood) may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels. 1 figure. 1 table. 13 references.

•

Clarifying the Role of Insulin in Type 2 Diabetes Management Source: Clinical Diabetes. 21(1): 14-20, 94. October 2002.

Studies

13

Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The prevalence of type 2 diabetes has been increasing rapidly and with it has been resultant morbidity (complications) and mortality (death). Strict glycemic control reduces the progression of diabetic microvascular disease; however, most patients treated with sulfonylureas (oral hypoglycemic agents) require additional insulin therapy. This article addresses common clinician concerns about prescribing insulin early in type 2 diabetes. The authors present strategies for incorporating basal insulin therapy with glargine (Lantus) into a regimen that promotes compliance. The authors note that several studies have clearly shown that basal insulin therapy, particularly using the insulin analog glargine, closely mimics the body's physiological secretion of basal insulin and may be added to an existing oral regimen, used alone, or used with preprandial (before a meal) insulin. 3 figures. 4 tables. 50 references. •

Homeostasis Model Assessment of Insulin Resistance in Relation to the Incidence of Cardiovascular Disease: The San Antonia Heart Study Source: Diabetes Care. 25(7): 1177-1184. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The prospective association between insulin levels and risk of cardiovascular disease (CVD) is controversial. The objective of the study reported in this article was to investigate the relationship of the homeostasis model assessment of insulin resistance (HOMA-IR), as well as insulin levels, with risk of nonfatal and fatal CVD over the 8 year follow-up of the San Antonio Heart Study. Between 1984 and 1988, randomly selected Mexican-American and nonHispanic white residents of San Antonio participated in baseline examinations that included fasting blood samples for glucose, insulin, and lipids, a glucose tolerance test, anthropometric measurements, and a lifestyle questionnaire. Between 1991 and 1996, 2,569 subjects who were free of diabetes at baseline were reexamined using the same protocol. Over the follow up period, 187 subjects experienced an incident cardiovascular event (heart attack, heart surgery, angina, or CVD death). The authors found a significant association between HOMA-IR and risk of CVD, after adjustment for multiple covariates. The topic remains controversial, however, and additional studies are required, particularly among women and minority populations. 3 figures. 3 tables. 41 references.

•

Improved Postprandial Glycemic Control with Biphasic Insulin Aspart Relative to Biphasic Insulin Lispro and Biphasic Human Insulin in Patients with Type 2 Diabetes Source: Diabetes Care. 25(5): 883-888. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The rapid acting insulin analogs aspart and lispro have now been developed in biphasic formulations. This article reports on a study that compared the postprandial (after a meal) serum glucose (blood sugar) control of biphasic insulin aspart 30 with that of biphasic insulin lispro 25 and biphasic human insulin 30 in insulin-treated people with type 2 diabetes. This open labeled, randomized, single-dose, three way crossover trial included 61 subjects who had no significant late diabetic complications. The

14

Insulin

postprandial glycemic control with BIAsp 30 was superior to that with both BHI 30 and Mix25 in subjects with type 2 diabetes. 2 figures. 1 table. 29 references. •

Counseling Patients With Type 2 Diabetes and Insulin Resistance in the Outpatient Setting Source: Diabetes Educator. 28(6): 938,940-943,947-950,952-954,956-957. NovemberDecember 2002. Contact: Available from American Association of Diabetes Educators (AADE). 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: The task of self management of diabetes can be daunting for patients because it requires making significant lifestyle and behavioral changes and involves frequent visits to health care professionals, regular blood glucose monitoring, complex drug regimens, and vigilant treatment of complications. This article describes the role of counseling for patients with type 2 diabetes and insulin resistance, to provide the essential support and encouragement for patients to successfully manage their disease. The article focuses on insulin resistance which, besides being a leading risk factor for type 2 diabetes, is also associated with hypertension, dyslipidemia, obesity, and cardiovascular disease. Making lifestyle changes can reduce insulin resistance and help prevent the onset of diabetes. For those with type 2 diabetes, treatment with insulinsensitizing drugs, such as the TZDs and biguanides, can improve glycemic control and prevent some of the adverse consequences of the disease. Adherence to both lifestyle and medication regimens is very important and should be actively supported by all members of the health care team. 2 figures. 8 tables. 52 references.

•

Selecting Children and Adolescents for Insulin Pump Therapy: Medical and Behavioral Considerations Source: Diabetes Spectrum. 15(2): 72-75. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The use of continuous insulin therapy via a subcutaneously implant catheter connected to an external pump is being used increasingly in the management of childhood type 1 diabetes. This form of intensive diabetes management places multiple demands on young patients to achieve near-normal blood glucose levels. Therefore, appropriate selection of pediatric candidates for pump therapy is critical to achieving successful outcomes. This article explores this aspect of patient selection, using an illustrative case report of a 10 year old boy with a 3 year history of type 1 diabetes. The focus of this case presentation is to describe key factors for health care professionals to consider in helping children and adolescents make the transition to the insulin pump. The authors use their experiences based on the pediatric pump program at Children's National Medical Center in Washington, D.C. In addition to an accurate patient selection process, other factors important to long term success with insulin pumps include the ongoing support, management, and interplay between patients, families, and the diabetes team. 13 references.

•

Insulin Resistance and Insulin Secretory Dysfunction Are Independent Predictors of Worsening of Glucose Tolerance During Each Stage of Type 2 Diabetes Development Source: Diabetes Care. 24(1): 89-94. January 2001.

Studies

15

Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a study that assessed the predictive effect of insulin resistance and insulin secretory dysfunction separately for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and from IGT to diabetes. Insulin-stimulated glucose disposal (M), acute insulin secretory response (AIR), and body composition were measured in 254 Pima Indians with NGT and in 145 Pima Indians with IGT, who were then followed for 0.5 to 13 years. The study found that, after followups of 4.4 plus or minus 3.1 and 5.5 plus or minus 3.4 years, 79 of the subjects with initial NGT had developed IGT, and 64 of the subjects with initial IGT had developed diabetes. In proportional hazards analyses with adjustment for age, gender, and percent body fat, low M and low AIR were independent predictors of both the progression from NGT to IGT and from IGT to diabetes. The article concludes that, during each stage of the development of type 2 diabetes, insulin resistance and insulin secretory dysfunction are independent predictors of worsening glucose tolerance and are, therefore, both targets for the primary prevention of the disease. 1 figure. 2 tables. 20 references. (AA-M). •

Insulin Lispro Update Source: Diabetes Educator. 28(2): 269-277. March-April 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article provides a review of the literature and clinical studies for insulin lispro and updated information on its advantages over regular insulin for various populations of people with diabetes. Information was gathered from a search of Medline articles and from review of clinical studies. Patients in various special populations using insulin lispro, with proper adjustment of basal insulin, had a greater reduction in hemoglobin A1c (glycosylated hemoglobin, a measure of blood glucose over time), and fewer episodes of hypoglycemia than patients on regular insulin. More recently published literature shows that due to its faster onset and shorter duration of action, insulin lispro is useful for not only lowering A1c values, but also for reducing hypoglycemic (low blood glucose) events in various populations with diabetes, including pediatric and pregnant patients, those with gastroparesis, and insulin pump users. 3 figures. 3 tables. 18 references.

•

Insulin Self-Administration Instruction: Use of Engineered Sharps Inquiry Protection Devices to Meet OSHA Regulations Source: Diabetes Educator. 28(5): 730-734. September-October 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article provides the official position statement of the American Association of Diabetes Educators (AADE) on insulin self-administration instruction and use of engineered sharps injury protection devices in order to meet OSHA (Occupational Safety and Health Administration) regulations. The article reviews the provisions of the Needlestick Safety and Prevention Act and then outlines the impact of OSHA regulations on diabetes care and education practices. Seven recommendations are noted: Any injection administered to the patient by a health care worker will be delivered using engineered sharps injury protection (ESIP) insulin syringes;

16

Insulin

individualized patient assessment will guide the health care provider's decision regarding use of ESIP syringes during insulin self-administration; the physical environment where insulin self-administration education occurs should allow for reasonable physical distance between the patient and health care worker to reduce inadvertent needlesticks; a sharps disposal container should be readily available; the patient or significant other should receive instruction regarding appropriate disposal of all sharps in the home setting; the process of educating patients must address individual patient needs without compromising health care worker safety; and all health care entities must have a written exposure control plan. 5 references. •

Immune Responses to Insulin Aspart and Biphasic Insulin Aspart in People with Type 1 and Type 2 Diabetes Source: Diabetes Care. 25(5): 876-882. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study in which the antibody responses to a new rapid-acting insulin analog (insulin aspart, IAsp) and their potential clinical correlates were investigated with a specifically developed method in 2,420 people with diabetes treated for up to 1 year with preprandial (before a meal) subcutaneous injections of IAsp. Insulin antibodies specific to human insulin (HI) or IAsp were absent in a majority of patients throughout the 6 to 12 month study periods. A majority of the patients (64 to 68 percent) had antibodies cross reacting between HI and IAsp when entering the studies. Antibody levels showed similar changes in people with type 1 and type 2 diabetes, and there was no consistent relationship between antibody formation and glycemic control or between antibody formation and safety in terms of adverse events. The authors conclude that treatment with IAsp is associated with an increase in cross reactive insulin antibodies, with a subsequent fall toward baseline values, without any indication of clinical relevance because no impact on effectiveness or safety could be identified. 1 figure. 6 tables. 23 references.

•

Effect of Long-term Exposure to Insulin Lispro on the Induction of Antibody Response in Patients with Type 1 or Type 2 Diabetes Source: Diabetes Care. 26(1): 89-96. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study of the long-term effects of insulin lispro on induced lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies. The multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years' duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12 to 81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays. The results showed that the immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin. 5 figures. 2 tables. 46 references.

Studies

•

17

Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes and Insulin Resistance Source: Diabetes Care. 26(1): 138-143. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that evaluated whether, in adolescents with type 1 diabetes, the addition of metformin to insulin and standard diabetes management results in higher insulin sensitivity and lower HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time), fasting glucose, insulin dosage, and body mass index (BMI). This randomized, placebo-controlled 3 month trial of metformin therapy included 27 adolescents with type 1 diabetes, high insulin dosage, and HbA1c greater than 8 percent. Results showed that metformin treatment lowered HbA1c and decreased insulin dosage with no weight gain in teens with type 1 diabetes in poor metabolic control. Changes in insulin sensitivity were not documented in this study. 1 figure. 2 tables. 32 references.

•

Prediction of Type 2 Diabetes Using Simple Measures of Insulin Resistance Source: Diabetes. 52(2): 463-469. February 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to determine and formally compare the ability of simple indices of insulin resistance (IR) to predict type 2 diabetes. The authors used combined prospective data that included well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5 to 8 years of follow up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow up examination (343 of 3,574 subjects developed diabetes). The authors found substantial differences between published IR indexes in the prediction of diabetes, with ISI 0,120 consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR. 6 tables. 28 references.

•

Cardiovascular Safety of Oral Antidiabetic Agents: The Insulin Secretagogues Source: Clinical Diabetes. 20(2): 81-84. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reviews and dispels concerns about the potential cardiotoxicity (damaging to the heart) of insulin and oral diabetes drugs, specifically the insulin secretagogues, in patients with type 2 diabetes. The authors focus on insulin and the sulfonylurea drugs but also briefly discuss meglitinide analogs. The authors note that the majority of experimental evidence in humans suggests that, in patients with type 2 diabetes, tighter glycemic control decreases cardiovascular events, even though patients' intensive treatment results in higher plasma insulin levels. In addition, tighter glycemic (blood glucose) control clearly has been shown to decrease the risk of microvascular complications such as retinopathy (eye disease) and nephropathy (kidney disease) as well as neuropathy (nerve disease). Thus, the beneficial effect is sufficient justification to recommend tight glycemic control in patients with type 2 diabetes. 28 references.

18

Insulin

•

Enhancement of Memory in Alzheimer Disease With Insulin and Somatostatin, But Not Glucose Source: Archives of General Psychiatry. 56: 1135-1140. December 1999. Summary: This journal article describes a study that examined whether memory improvement is due to changes in insulin, independent of hyperglycemia, in patients with Alzheimer's disease (AD). Twenty-three patients with AD and 14 healthy controls were tested under 4 metabolic conditions on separate days: hyperinsulinemia while maintaining glucose at a fasting level; hyperglycemia while maintaining insulin at a fasting level by concomitant administration of the somatostatin analogue octreotide; fasting levels of insulin and glucose maintained by infusion of isotonic sodium chloride (saline) solution; and an active control condition in which somatostatin was administered alone while glucose and insulin remained at fasting levels. Declarative memory and selective attention were measured under each condition. The AD patients showed significantly improved memory during hyperinsulinemia compared with both placebo and hyperglycemia. Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory in patients with AD. The results indicate that insulin is essential for hyperglycemic memory facilitation, and suggest a potential therapeutic role for somatostatin in AD. 2 figures, 4 tables, 39 references.

•

Avoiding Insulin Errors Source: Clinical Diabetes. 20(4): 223-224. October 1, 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This patient education handout assists readers in avoiding insulin errors. The author notes that errors in handling and administering insulin can be easy to make, especially if the patient uses more than one kind of insulin to manage their diabetes. The hand out offers and explains four suggestions: know the insulin product, measure carefully, store safely, and consult a health care provider before mixing insulins. One chart summarizes the different types of insulin currently available, with the following information provided for each: source, color, and approximate length of action (onset, peak, and maximum). The chart caption notes that all times are approximate and may differ with each individual and vary with site and other factors. 1 table.

•

Control of Postprandial Hyperglycemia: Optimal Use of Short-Acting Insulin Secretagogues Source: Diabetes Care. 25(12): 2147-2152. December 2002. Contact: Available from American Diabetes Association (ADA). 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study was designed to compare the efficacy of acute premeal administration of glipizide versus nateglinide in controlling postprandial (after a meal) hyperglycemia in subjects with non-insulin- requiring type 2 diabetes. A total of 20 subjects (10 female, 10 male) with non-insulin-requiring type 2 diabetes were admitted overnight to the General Clinical Research Center on four occasions. The subjects were aged 56 years, plus or minus 2 years, and were moderately obese, with a mean HbA1c of 7.4 percent. Peak and integrated glucose excursions did not differ significantly between glipizide and nateglinide. However, by 4 hours postmeal, plasma glucose levels were significantly higher with nateglinide compared with the premeal baseline and compared

Studies

19

with the 4 hour postprandial glucose level after administration of glipizide. Early insulin secretion, as measured by insulin levels at 30 minutes postmeal, did not differ between glipizide and nateglinide. The authors conclude that the clinical decision to use glipizide versus nateglinide should be based on factors other than the control of postprandial hyperglycemia in type 2 diabetes. 3 figures. 1 table. 25 references. •

Insulin Resistance and Associated Compensatory Responses in African-American and Hispanic Children Source: Diabetes Care. 25(12): 2184-2190. December 2002. Contact: Available from American Diabetes Association (ADA). 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study was undertaken to compare insulin resistance relative to body fat and the associated compensatory responses in 57 healthy children living in Los Angeles, California (14 Caucasians, 15 African-Americans, and 28 Hispanics). Insulin sensitivity and acute insulin response were determined by intravenous glucose tolerance test. Insulin secretion, hepatic insulin extraction, and insulin clearance were estimated by Cpeptide and insulin modeling. Results showed that insulin sensitivity was significantly lower in Hispanics and African-Americans compared with Caucasian children, and acute insulin response was significantly higher in African-American children. No ethnic differences were noted in the first-phase secretion, but second phase insulin secretion was significantly higher in Hispanic children than in African-American children. The greater acute insulin response in African-Americans, despite lower secretion, was explained by a lower hepatic insulin extraction in African-Americans compared with Hispanics. The authors conclude that Hispanic and African-American children are more insulin resistant than Caucasian children, but the associated compensatory response are different across ethnic groups. 1 figure. 2 tables. 25 references.

Federally Funded Research on Insulin The U.S. Government supports a variety of research studies relating to insulin. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to insulin. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore insulin. The following is typical of the type of information found when searching the CRISP database for insulin:

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

20

Insulin

•

Project Title: ALKYLGLYCOSIDE FORMULATIONS FOR NASAL INSULIN DELIVERY Principal Investigator & Institution: Pillion, Dennis J.; Associate Professor; Cytrx Corporation 154 Technology Pky, Ste 200 Norcross, Ga 30092 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-MAY-2002 Summary: Nasal insulin delivery remains a possible alternative for patients with diabetes mellitus in attempting to control blood glucose levels. Nasal insulin administration requires the addition of a surfactant agent to improve systemic absorption of insulin, but this requirement has led to difficulty in identifying safe, effective surfactant agents that could be included in a nasal formulation. Pilot studies by the investigators have shown that some alkylglycosides were effective in promoting insulin absorption following nasal delivery. Alkylglycosides with longer alkyl side chains (i.e. 12-14 carbons in length) were the most effective in enhancing insulin absorption, whereas alkylglycosides with shorter side chains (i.e. 6- 8 carbons in length) were ineffective. In Phase I of this investigation, alkylglycosides with side chains containing 14- 16 carbons were synthesized and their efficacy in enhancing nasal insulin delivery was determined. Tetradecylmaltoside, an alkylglycoside with a 14 carbon side chain, was the most effective reagent at increasing nasal insulin delivery. Independently, this reagent caused little nasal toxicity when applied to rats once a day for 15 days. The extent of the nasal toxicity was dependent on the tetradecylmaltoside concentration used. Phase II studies are intended to; l) assess the stability of nasal insulin formulations containing tetradecylmaltoside; 2) compare the efficacy of nosedrops containing insulin and tetradecylmaltoside verses nasal mist or aerosol of the same formulation in primarily rats (but also rabbits and monkeys too); 3) compare the onset and duration of action of nasal insulin delivery when rapid-acting insulin or intermediate-acting insulin are substituted for regular insulin. (Preliminary data in Appendix l indicates that monomeric LysPro-insulin, regular or NPH-insulin with 0.125% dodecylmaltoside were as efficiently absorbed as each other, giving similar pharmacokinetic/pharmakodynamic profiles); 4) determine the formulation to bring to clinical trials. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: AMP KINASE AND DAF 16--CHLORIC RESTRICTION OF LONGEVITY Principal Investigator & Institution: Alexander-Bridges, Maria C.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Genetic evidence in worms (C. Elegans) has shown that insulin-like molecules act via PI3 kinase and AKT/protein kinase B to inhibit the function of the forkhead (FKH) transcription factor DAF-16. Insulin signaling mutants with diminished function undergo dauer arrest and show increased longevity and resistance to oxidative stress due to the unimpeded action of DAF-16. Accordingly, DAF-16 has been shown to activate the superoxide dismutase gene (SOD). In mammals, caloric restriction and low insulin signaling has been shown to slow the rate of aging by mechanisms that include increased DNA repair capacity and reduction of oxidative stress. In the presence of low glucose and circulating insulin levels, DAF-16 homologues appear to be transcriptionally active. Several laboratories have shown that in the absence of insulin, mammalian homologues of DAF-16, FKHR, FKHRL1 and AFX activate the transcription of genes that control apoptosis, and gluconeogenesis, and

Studies

21

insulin can inhibit this effect. Our goal is to elucidate the mechanisms by which DAF-16 like factors activate transcription in the absence of insulin. Caloric restriction and low glucose activates AMP kinase. We find that AMP kinase can prevent the effect of insulin on DAF-16 in HepG2 cells. Furthermore, AMP kinase can directly phosphorylate DAF16. We propose to determine whether regulation of DAF-16 by AMP kinase in worms and regulation of its homologue FKHR in mammalian cells, can explain the ability of caloric restriction to slow the aging process. In HepG2 cells, insulin signaling via the AKT sites in DAF-16 inhibits DAF-16 activity. We find that the AKT sites in DAF-16 carry overlapping AMP kinase sites. In Specific Aim 1 of this proposal, we will determine whether AMP kinase regulates DAF-16 activity directly by altering its phosphorylation or indirectly by regulating other elements of the PI3 kinase-signaling pathway. We will examine the effect of AMP kinase on 1) phosph DAF-16 phosphorylation in vitro and in vivo, 2) 14-3-3 binding to DAF-16 in the presence and absence of insulin and 3) the interaction of DAF-16 with other proteins that increase its binding/transcription activity. In Specific Aim II we will determine whether AMP kinase can counteract the effect of insulin signaling to DAF-16 in C. elegans, and prolong life span in the worm. In Specific Aim III, we will examine the effect of caloric restriction and carbohydrate-induced hyperinsulinemia on the activity of AMP kinase and DAF-16 homologues Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE Principal Investigator & Institution: Rossetti, Luciano; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2001; Project Start 01-AUG-1994; Project End 31-JUL-2004 Summary: In this project, we propose to continue our investigation of the biochemical and molecular mechanism(s) by which "insulin resistance" is acquired. Our long-term focus has been on the potential link between nutrient excess and impairment of insulin action. In this regard, we have recently shown that increased nutrient (eg, carbohydrate and lipid) availability results in insulin resistance and in increased leptin gene expression via increased flux of carbons into the hexosamine biosynthetic pathway. We propose herein that a close loop feed-back regulation is normally operating between nutrients and their metabolic outcomes. Thus, nutrient excess is sensed via the hexosamine biosynthetic pathway and generates signals leading to decreased insulin action on glucose uptake and to increased leptin gene expression. They also favor increased storage into lipid via increased tissue levels of Malonyl-CoA and Long ChainCoA and ultimately increased adiposity and weight gain. However, the concomitant induction of leptin expression attempts to counteract this drive by antagonizing the effects of nutrients on Malonyl-CoA and triglyceride storage, on the hexosamine pathway and perhaps via direct effects on insulin signaling. Any disruption of this physiological response (due to either impaired stimulation of leptin expression by nutrients or to decreased effectiveness of leptin action on target tissues) is likely to lead to increased adiposity and more insulin resistance. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: 1. How do nutrients regulate insulin action? We will focus on the interaction between increased lipid availability and skeletal muscle insulin signaling and action. We hypothesize that the susceptibility to develop insulin resistance in response to excessive nutrient exposure is modulated by the skeletal muscle ability to utilize fructose-6-phosphate in the glycolytic pathway. 2. How does leptin modulate hepatic and muscle glucose/lipid metabolism and insulin action? We will examine whether specific hypothalamic targets

22

Insulin

of leptin play distinct roles in mediating its complex metabolic effects. 3. Is leptin synthesis and/or action modulated following prolonged stimulation? We will generate short-term models of relative hyperleptinemia and will test the hypothesis that the "protective" effect of leptin against nutrient excess wanes if the leptin signal/transduction system is chronically over-stimulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALORIC RESTRICTION, AGING, AND INSULIN ACTION Principal Investigator & Institution: Cefalu, William T.; Associate Professor of Medicine; Medicine; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Caloric restriction has been shown to extend the mean and maximal lifespan and slow the aging rate in a number of lower species, primarily mice and rats. In particular, the increase in maximal lifespan in mice and rats appears to depend primary on caloric restriction (CR) which is associated with later appearances and lowered incidence of most naturally occurring diseases. The mechanisms by which CR exerts its anti-aging effect are unknown. Recently, it was observed in a lower species that lifespan regulation and increased longevity by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction. Therefore, in light of the interest in mechanisms of action of CR, physiological validity, and possible application for human subjects, it has become essential to test caloric restriction in animal models that more closely resemble humans, particularly for age associated disease. Such is the aims of our non-human primate trail (e.g. Parent Trial) evaluating the effect of caloric restriction on an age associated disease (i.e. atherosclerosis). The hypothesis for the Parent Trial is that caloric restriction over an sustained period when compared to an ad lib diet, may delay the onset of atherosclerosis by reducing age associated increases in glycated products, reducing intra-abdominal fat, and improving insulin sensitivity. It is the improved insulin sensitivity that is noted as a consistent metabolic feature secondary to prolonged CR not only in rodent studies, but in on going trials assessing CR in higher species such as non-human primates including our Parent trial. The specific focus of this application is to evaluate potential cellular mechanisms by which caloric restrition may improve insulin action in vivo. Our working hypothesis is that signal transduction through insulin receptors is diminished with aging is improved secondary to crhonic CR. Our specific hypothesis is that caloric restriction improves insulin sensitivity by enhancing insulin receptor signal transduction. Specifically, we propoose CR improves insulin action by 1)enhancing insulin receptor substrate (IRS) phosphorylation and 3) enhancing IRS association with cytosolic substrates known to be involved with in vivo insulin action. Our specific aims to evaluate the mechanistic basis behind the enhanced insulin sensitivity inducecd by CR will be tested in tissues collected as part of a non-human primate caloric restriciton trial. These tissues have been processed and stored appropriately after both basal and in vivo insulin stimulated conditions and specific cellular signaling will be asessed The focus on cellular mechanisms by which CR may improve insulin sensitivity in higher species combined with the clinical and metabolic measuremetns obtained as part of a completed Parent Trial will provide a comprehnsive evaluation of how CR may alter glucose metabolism with age and is unique feature of this revised submission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

23

Project Title: CASEIN COATED CAP PARTICLES FOR ORAL INSULIN DELIVERY Principal Investigator & Institution: Morcol, Tulin; Biosante Pharmaceuticals, Inc 4600 Highlands Pky, Ste A&B Smyrna, Ga 30082 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): Parenteral administration of insulin via the subcutaneous route is the only commercially available therapy to treat insulindependent diabetes mellitus. Multiple daily injections are required to manage and maintain blood glucose control due to its relatively short duration of action (4 to 8 hours). Oral insulin would provide an attractive alternative. However, successful development of an oral insulin formulation has been hampered by the numerous and complex barriers to protein absorption inherent to the gastrointestinal tract. A novel delivery system has emerged that may overcome these obstacles. The design of this delivery system incorporates an understanding of the complex barriers to oral insulin absorption and results in the production of biodegradable, insulin-impregnated, calcium phosphate / polyethylene glycol microparticles coated with casein. The characterization of particle size and morphology, their associated physicochemical properties, and the critical factors affecting these parameters will assist in formula optimization and process development. Thus, the aims of Phase I are to prepare a lot of casein coated, insulinladen microparticles utilizing the most current manufacturing process; to fully characterize them in terms of particle size, particle morphology, % loading of insulin, insulin activity, relative component composition, moisture content, stability against digestive enzymes, pH-dependent dissolution characteristics, and storage stability; and to demonstrate a dose-dependent reduction in blood glucose with concomitant increase in serum insulin levels in rodents. Furthermore, modification and adaptation of the delivery system to another orally challenged therapeutic protein, such as human growth hormone, would demonstrate general utility of the delivery system. The long-range goal of this research is to develop a novel, safe, efficacious, long-acting, oral delivery system for insulin demonstrating a dose dependency with reduced variability that may be applicable to other therapeutically relevant proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CAVEOLAE IN INSULIN SIGNALLING Principal Investigator & Institution: Mastick, Cynthia C.; Biochemistry; University of Nevada Reno Reno, Nv 89557 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-JUL-2003 Summary: The long-term objective of this proposal is to increase our knowledge of the cellular mechanisms of insulin action. When insulin binds to its receptor at the cell surface signals are transmitted to the enzymes regulated by insulin through signal transduction cascades. However, the molecular details of these pathways remain incompletely understood. Defects in these signalling cascades lead to peripheral insulin resistance and the development of type II diabetes mellitus, a common and devastating disease in this country. In almost all patients these defects lie downstream of the insulin receptor itself. A more complete understanding of insulin-stimulated signalling pathways will lead to a greater understanding of the underlying causes of insulin resistance and diabetes, and potentially to identification of better targets for the treatment of this disease. The focus of this proposal is the characterization of a unique insulin-stimulated signalling pathway involving tyrosine phosphorylation of caveolin. Caveolin is a structural component of specialized cell surface domains termed caveolae. This phosphorylation is both insulin-specific and cell type-dependent, occurring only in

24

Insulin

cells that are highly insulin responsive. These properties suggest that this pathway may play a key role in the cellular effects of insulin. The 3T3-L1 cell culture model of adipocytes was chosen for its convenience and extraordinary insulin-responsiveness, particularly in the regulation of glycogen metabolism. To obtain large amounts of material for protein isolation the cultured primary adipocyte system will also be used. The specific aims of this proposal are to: 1. Determine the signalling pathway leading to caveolin phosphorylation through the heterologous expression of wild type and mutant forms of candidate upstream signalling molecules. 2. Identify proteins that bind phosphorylated caveolin using biochemical and molecular approaches. 3. Determine the effect of environmental factors on caveolin phosphorylation through the manipulation of experimental conditions. 4. Correlate caveolin phosphorylation with known cellular effects of insulin using heterologous expression of signalling molecules to modulate caveolin phosphorylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTRAL/PERIPHERAL TARGETS FOR METABOLIC ACTIONS OF LEPTIN Principal Investigator & Institution: Kahn, Barbara B.; Chief; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2002 Summary: The overall goal of this proposal is to understand the molecular mechanisms underlying the effect of leptin to rapidly enhance insulin sensitivity independent of its effects on food intake and body weight. We will investigate the contribution of CNSmediated and direct effects at the level of peripheral tissues. In Aim 1 we will determine whether insulin and leptin share common intracellular signal transduction pathways. With i.v. administration of leptin in rats, we will test the hypothesis that the insulinsensitizing effects of leptin involve convergence of synergism between leptin-activated and insulin-activated signal transduction pathways. We will determine the time course for leptin activation of phosphorylation of the insulin receptor and IRSs and activation of PI3 kinase, MAPK kinase and Stat1 and Stat in insulin target tissues (skeletal muscle, BAT, WAT liver) in vivo. We will investigate potential additive effects of leptin and insulin. In Aim 2 we will test the hypothesis that early activation of signaling pathways by leptin results from direct effects the level of the target tissues but later effects involve CNS mediation as well. We will measure activation of signaling pathways in the hypothalamus after iv or ICV leptin over a time course. We will determine which effects are present after sympathectomy of skeletal muscle or BT. We will determine which signaling pathways are activated in vitro in adipocytes and muscle. In Aim 3 we will test the hypothesis that some of the biological actions of leptin are exerted directly at the level of the adipocyte. We will generate transgenic db/db mice expressing the leptin receptor selectively in fat using the aP2 promoter/enhancer. We will determine whether restoration of long form leptin receptors exclusively in adipocytes alters adipocyte physiology, glucose homeostasis, or insulin action. In im 4 we will test the hypothesis that specific hypothalamic nuclei are involved in the insulin-sensitizing effects of leptin. We will microinject leptin into the DMH, VMH and PVH and measure glucose disposal by euglycemic clamp and glucose uptake into specific muscles and adipose depots in vivo. Thus, we will map the regions of insulin sensitivity. These studies will yield important information about the direct and CNS-mediated mechanisms by which leptin enhances insulin sensitively and may lead to new avenues for treatment of obesity and diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

25

Project Title: COUPLING OF D-CHIRO-INOSITOL TO INSULIN IN PCOS WOMEN Principal Investigator & Institution: Iuorno, Maria J.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation and it is the most common form of female infertility in the U.S. It has been demonstrated that insulin resistance accompanied by compensatory hyperinsulinemia is, in part, responsible for the hyperandrogenism and anovulation of this disorder. The cellular mechanisms of insulin resistance in PCOS are still largely unknown. D-chiro-inositol phosphoglycan (DCI-IPG) is a nonclassical mediator of insulin action that has been demonstrated to increase glucose utilization. Previous studies have shown that administering a drug similar to the native mediator to women with PCOS increases insulin sensitivity, reduces ovarian androgen production and improves ovulation in these women. Therefore, it seems likely that women with PCOS have a defect in DCI-IPG cellular activity that leads to insulin resistance. The aim of this application is to determine whether a defect in coupling between D-chiro-inositol phosphoglycan and insulin plays a role in the insulin resistance of PCOS. We propose to assess the coupling of the DCI-IPG to insulin in women with PCOS and normal women: 1) by administering diazoxide to these women in order to temporarily suppress their pancreatic insulin secretion and measure a change in activity in DCI-IPG in plasma of these women following suppression of insulin and 2) by restoring insulin following diazoxide administration using an insulin clamp and measuring the degree to which DCI-IPG activity is also restored during the clamp in normal women versus women with PCOS. Hence, both PCOS women and normal control women will be evaluated for this insulin to DCI-IPG activity relationship. It is our hypothesis that at least one mechanism of insulin resistance in PCOS is due to defective coupling between insulin and DCI-IPG activity. The results of these studies will 1) describe the physiologic, in vivo relationship between insulin and DCI-IPG in normal women; 2) provide a mechanism for insulin resistance in PCOS as it relates to the DCI-IPG insulin signaling cascade; 3) provide the groundwork for further clinical studies to explore the role of defective coupling in other insulin resistant human conditions (such obesity or type 2 diabetes); and 4) lead to novel specific therapies for the insulin resistance of PCOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DESIGN AND USE OF METHODS FOR PEPTIDE SECRETION STUDIES Principal Investigator & Institution: Kennedy, Robert T.; Hobart H. Willard Professor; Chemistry; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-MAR-2006 Summary: Type 2 diabetes is a leading cause of death in the US and its incidence is rapidly rising. This disease is associated with insulin resistance (ineffective use of insulin) and impaired insulin secretion from pancreatic beta cells. These cells are found in small clusters of approximately 2000 cells known as islets of Langerhans. In most forms of type 2 diabetes, the defects leading to impaired insulin secretion are unknown. A greater understanding of insulin secretion would be invaluable in identifying possible defects associated with diabetes. It is known that metabolism of glucose generates a variety of second messengers (small intracellular molecules) including ATP

26

Insulin

and Ca2+ that ultimately evoke secretion; however, the current model cannot explain observations such as oscillations in secretion and possible links between insulin resistance and insulin secretion. In this work, we propose to develop novel analytical tools for studying insulin secretion at the level of single cells and single islets. These tools include: 1) a microfabricated workstation that incorporates sensors and a highspeed capillary electrophoresis system for simultaneous monitoring of metabolic changes, second messenger level, and insulin secretion with high temporal resolution; 2) novel chromatographic assays for second messengers; and 3) a technique for imaging secretion around a cell. These novel analytical instruments and methods will play an important role in determining the normal molecular mechanisms of insulin secretion and possible defects associated with diabetes. In this work, these tools will be used to study the oscillatory behavior of isle and the role of insulin in controlling insulin secretion through a feedback loop. These issues are both at the forefront of beta-cell research as loss of oscillations are a key event in onset of diabetes and insulin feedback through insulin receptors on the beta cell is a possible link between impaired insulin secretion and insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES MECHANISMS

IN

HEMOCHROMATOSIS:

PREVALENCE

AND

Principal Investigator & Institution: Mcclain, Donald A.; Professor and Director; Internal Medicine; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-OCT-2006 Summary: Although the hemochromatosis gene (HFE) has been identified there is little information about the diabetes that often accompanies the disease. We hypothesize nondiabetic homozygotes for mutations in HFE will exhibit a defect in insulin secretion as iron overload develops. This notion is supported by preliminary data obtained in HFE mutant mice. The insulin deficiency will progress to type 2 diabetes only if insulin resistance also occurs, either from cirrhosis or inheritance of type 2 diabetes genes. Insulin resistance from cirrhosis is hypothesized to result from excess carbohydrate delivery to peripheral tissues, resulting in excess hexosamine generation, an established cause of insulin resistance. Our specific aims are to: 1. Determine the prevalence of impaired glucose intolerance (IGT) and diabetes in clinically unselected individuals with hemochromatosis by oral glucose tolerance criteria. 2. Determine if a defect in insulin secretion exists in nondiabetic homozygotes with or without iron overload. This will be accomplished using the frequently sampled intravenous glucose tolerance test (FSIVGTT) with insulin levels. Reversibility of the defect will be examined after subjects have undergone phlebotomy. The hypothesis will be verified in studies of isolated islets from mice carrying disrupted or mutant HFE genes. 3. Using animal models, determine if diabetes in hemochromatosis results only when insulin resistance is superimposed on an iron- mediated defect in insulin secretion. 4. Determine the sequence and relative contributions of insulin resistance and hepatic glucose production (HGP) in the evolution of diabetes in human hemochromatosis. Insulin resistance and HGP will be quantified by the hyperinsulinemic euglycemic clamp and stable isotope techniques in subjects with hemochromatosis who have normal or IGT, with or without hepatic involvement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

27

Studies

•

Project Title: DIET METABOLISM

AND

EXERCISE:

RACE,

POSTMENOPAUSE

AND

Principal Investigator & Institution: Ryan, Alice S.; Associate Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (Verbatim from application) African American women are more obese and insulin resistant than Caucasian women. This research is designed to determine whether overweight African American women respond differently to hypocaloric weight loss (WL) or aerobic exercise plus weight loss (AEX+WL) than do Caucasian women. The hypothesis is that ethnic differences (African American vs. Caucasian) in the mechanisms by which WL affects insulin sensitivity in overweight, insulin resistant African American postmenopausal women requires that the WL be accompanied by AEX in African American women to improve insulin sensitivity. Specific aims determine 1) the race effects of WL vs. AEX+WL on insulin action on glucose and fat metabolism in African American compared to Caucasian women by assessing insulin sensitivity (EC50), and FFA suppression during hyperinsulinemia; and 2) the cellular mechanisms by which the addition of AEX to WL affects insulin sensitivity in African American compared to Caucasian women by ascertaining the effects of WL vs. AEX+WL on proteins affecting insulin action (GLUT4, IRS 1 and Pl-3 kinase) in skeletal muscle, and insulin suppression of lipolysis in adipocytes. We will study healthy, overweight (Body Mass Index, 27-35 kg/rn2) 50-60 year old postmenopausal African American and Caucasian women. Metabolic studies will be performed before and after either hypocaloric weight loss treatment (n=30 per race) or aerobic exercise training plus weight loss (n=30 per race). Insulin sensitivity and free fatty acid concentrations will be determined during a 3-step hyperinsulinemic-euglycemic clamp. We will measure total body fat (DXA scans), visceral fat and mid-thigh low density lean tissue (CT scans), glucose and insulin responses during an oral glucose tolerance test, skeletal muscle GLUT4, IRS 1, Pl 3-kinase, and insulin suppression of lipolysis in adipocytes. These findings may provide a rationale for targeting specific populations of women who might improve glucose and fat metabolism more from the addition of exercise to hypocaloric weight loss than weight loss alone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF ETHANOL ON INSULIN SIGNALING IN THE BRAIN Principal Investigator & Institution: De La Monte, Suzanne M.; Associate Professor of Pathology/Med; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Chronic gestational exposure to ethanol is teratogenic and causes major structural abnormalities in the central nervous system (CNS) including microcephaly and cerebellar hypoplasia. Insulin mediates CNS growth, development, and function, and ethanol has profound inhibitory effects on insulin signaling in neuronal cells. Using in vitro exposure models, we detected ethanol inhibition of insulin signaling, beginning at the level of its receptor and extending downstream through pathways that regulate neuronal survival. Importantly, ethanol inhibition of insulin-stimulated tyrosyl phosphorylation of the insulin receptor substrate-1 (IRS1) and downstream activation of PI3 kinase have been linked neuronal cell death mediated by impaired survival mechanisms, increased apoptosis, and mitochondrial (Mt) dysfunction. Recent preliminary experiments showed that cerebellar hypoplasia caused by chronic gestational exposure to ethanol is associated with similar

28

Insulin

types but probably greater degrees of impaired insulin signaling, and that neuronal loss is mediated by both apoptosis and Mt dysfunction. In addition, we obtained evidence that ethanol impairs signaling through both IRS1-dependent and IRS1-independent pathways in the developing brain. Since gestational exposure to ethanol does not inhibit insulin receptor protein expression, we hypothesize that the impaired insulin signaling is mediated by abnormalities in receptor function related to binding affinity, phosphorylation, or tyrosine kinase activation. Further studies are required to understand the mechanisms by which ethanol exerts its adverse effects on insulinstimulated viability and Mt function during development, and determine the degree to which similar abnormalities occur with different levels of ethanol exposure. In this application, we propose to: 1) examine the degrees to which low, moderate, or high levels of chronic gestational ethanol exposure impair insulin stimulated neuronal viability and Mt function; 2) determine the mechanisms by which ethanol causes Mt dysfunction or apoptosis; 3) characterize the insulin signaling pathways that are inhibited by chronic gestational exposure to ethanol; and 4) validate the roles of specific impairments as mediators of neuronal Mt dysfunction. The studies will utilize insulinstimulated post-mitotic primary cerebellar granule neuron cultures generated from ethanol-exposed and control rat pups since the cerebellum is a major target of ethanol neurotoxicity and cerebellar granule neurons are both responsive to insulin and functionally impaired by ethanol. These investigations could lead to new approaches for rescuing neuronal cells from the adverse effects of chronic gestational exposure to ethanol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOMETRIAL CANCER CHEMOPREVENTION STRATEGY FOR OBESE WO Principal Investigator & Institution: Lu, Karen H.; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: Obesity affects over 25% of adult women in the United States and continues to increase in prevalence. Minority women are disproportionately affected by obesity: 37% of African American women and 33% of Mexican American women are obese (body mass index equal to or more than 30 kg/m2). In addition to cardiovascular risks, obese women clearly are at increased risk for developing endometrial cancer. Obese women have a 9-10% lifetime risk of endometrial cancer and account for almost 50% of all cases. It is presumed that the increased peripheral conversion of adrenal steroids to estrone in adipose tissue, the increased bioavailability of adrenal steroids, and the increased bioavailablity of free estrogens due to decreased sex hormone binding globulin (SHBG) contribute to a "hyper-estrogenic state", resulting in the development of endometrial hyperplasia and endometrial cancer. However, excess circulating estrogens are unlikely to fully account for this increased cancer risk. We hypothesize that insulin resistance and hyperinsulinemia are causally related factors that promote endometrial carcinogenesis by altering estrogen regulated pathways in the endometrium. In addition, we hypothesize that correction of insulin resistance may be a rational cancer chemopreventive strategy for obese women. We plan to identify, using an animal model of obesity and insulin resistance, molecular markers in the endometrium associated with dysregulated estrogen-controlled growth pathways. A clinical chemoprevention trial will be performed to determine if normalization of insulin resistance is accompanied by modulation of surrogate biomarkers. Aim 1: To test the hypothesis that obesity and insulin resistance increase estrogen-dependent

Studies

29

proliferation in the endometrium. Animal models of obesity and insulin resistance will be used to evaluate the effects of obesity on estrogen-regulated endometrial gene expression. In addition, the ability of insulin sensitizers to reverse this effect will be studied. Specific genes involved in estrogen-regulated proliferation pathways will be examined by quantitative PCR, including hormone receptors and co-activators, and genes involved in the Wnt pathway, IGF pathway, TGF-beta and retinoid pathway. Aim 2: To identify novel genes and pathways associated with insulin resistance and estrogenization, and to identify relevant and specific biomarkers that are modulated by normalization of insulin resistance. Expression profiling with cDNA microarrays will be used to explore the effects of obesity and insulin resistance on both estrogen-dependent and estrogen-independent endometrial gene expression. In addition, specific biomarkers of the endometrium that are modulated by insulin-sensitizers will be identified. Aim 3: To assess the ability of an insulin-sensitizing agent to modulate surrogate endometrial biomarkers in a post-menopausal cohort of obese, insulin resistant women. The postmenopausal cohort includes obese women (body mass index equal to or more than 30kg/m2) who demonstrate insulin resistance based on an oral glucose tolerance test, but who do not fulfill criteria for Type II Diabetes. We hypothesize that rosiglitazone, an insulin-sensitizing agent, will modulate relevant endometrial proliferation biomarkers. In pre-and post-treatment endometrial biopsies, we will assess expression levels of genes involved in estrogen-regulated gro,aedapathways, specific biomarkers as defined in Aim 2, and histologic and proliferation markers. As secondary endpoints, we will establish a point estimate of the baseline frequency of endometrial abnormalities in this cohort and we will determine changes in serum levels of estradiol, estrone, testosterone, DHEA-S and SHBG in obese, post-menopausal women taking rosiglitazone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESISTANCE

ENDOTHELIAL

ABNORMALITIES

IN

OBESITY/INSULIN

Principal Investigator & Institution: Desouza, Christopher A.; Assistant Professor; Integrative Physiology; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Impairments in vascular endothelial function, particularly endothelium-dependent vasodilation, occurring in insulin resistant prediabetic states are thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelial vasodilatory dysfunction presents early in the pathogenesis of vascular disease, and contributes to the manifestation of atherogenic lesions, vasospasm, plaque rupture, intimal growth, and, in turn, coronary and cerebrovascular events. Moreover, forearm endothelial vasodilator dysfunction has been shown to be a marker of future cardiovascular events. Thus, a better understanding of the mechanisms responsible for the loss in endothelial vasodilator function associated with insulin resistance may lead to new targets for therapeutic intervention. Accordingly, the specific aims of the present proposal will be to determine: 1) if the blunted forearm endothelial vasodilator response to acetylcholine observed with obesity/insulin resistance reflects a specific agonist-related defect or rather a more general endothelial vasodilator abnormality; 2) whether the blunted forearm endothelial vasodilator response to acetylcholine observed with obesity/insulin resistance is related to: (a) decreased responsiveness to acetylcholine; (b) increase cholinesterase activity; (c) a selective impairment in stimulated nitric oxide release; (d) reduced muscarinic receptor function and/or number; and 3) if a program of regular endurance exercise improves endothelial vasodilator function, and whether the improvement is associated

30

Insulin

with increased insulin sensitivity. To address these aims, 180 middle-aged and older obese/insulin resistant and non-obese/insulin sensitive adults will be studied. Endothelium-dependent vasodilation will be assessed by changes in forearm blood flow (FBF: plethysmography) in response to intrabrachial infusions of acetylcholine, substance P, bradykinin, isoproterenol and methacholine. These endothelial agonists stimulate endothelial NO release via different cell surface receptors and intracellular Gprotein-mediated signal transduction pathways. FBF responses to some agonists will also be determined in the presence of either NG.monomethyl arginine (nitric oxide synthase inhibitor) or atropine (muscarinic receptor blocker) to address specific aim 2c and 2d. Endothelial vasodilator function will also be assesed after a 3-month aerobic exercise program in a subgroup of obese/insulin resistant adults. The results of the proposed study should provide mechanistic insight into whether forearm endothelial vasodilator dysfunction in obese/insulin resistant adults is related to a specific receptor defect or a more general endothelial abnormality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGENS AND INSULIN RESISTANCE IN WOMEN Principal Investigator & Institution: Olefsky, Jerrold M.; Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): There are genetic and environmental causes of insulin resistance, and clearly these two inputs can be additive and interactive. A high fat intake is an important environmental factor which can cause, or exacerbate, insulin resistance and enhance the risk for the development of Type II diabetes. Our recent studies have shown that lipid/heparin infusions lead to insulin resistance in men, but not in pre-menopausal women. We also have preliminary data showing that postmenopausal women are fully susceptible to fat-induced insulin resistance and that estrogen replacement therapy re-establishes the protective state. In addition, we have conducted a series of studies in rats, demonstrating that estrogenization (endogenous or exogenous) will protect females from fat -induced insulin resistance. Based on these findings, we propose that men and non-replaced post-menopausal women will exhibit fat-induced insulin resistance, whereas, adequately estrogenized women will be protected. We will test these ideas, not only by employing the lipid/heparin infusion glucose clamp technique, but also by placing experimental subjects on control and high fat diets. It is also possible that adequate estrogen can ameliorate the effects of other physiologic causes of insulin resistance. Thus, we also will conduct studies to determine whether estrogenization can protect women from the insulin resistance induced by obesity and aging. Using muscle biopsy samples collected during the glucose clamp studies, we will conduct experiments aimed at identifying cellular mechanisms for these protective effects of estrogens. We also propose an extensive series of animal studies, in which we will explore in more detail the mechanisms of estrogen protection from fatinduced insulin resistance. We will conduct studies in normal male and female rats, ovariectomized rats, and old estrogen deficient female rats+/- treatment with estradiol, an estrogen antagonist, or estrogen receptor isoform specific agonists. Studies in mice with deletion of the alpha or beta forms of the estrogen receptor, as well as muscle specific estrogen receptor specific knockout animals are also proposed. We will also determine whether the fat cell secreted protein ACRP3O is modulated by estrogen status, and whether the insulin sensitizing effects of ACRP3O are responsible for the estrogen induced protection from insulin resistance. If the concepts contained in this application prove correct, then these findings could have significant implications

Studies

31

concerning the mechanisms of insulin resistance as well as the treatment and possibly prevention of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FACTORS THAT MODIFY INSULIN ACTION Principal Investigator & Institution: Buse, Maria G.; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 01-MAY-1978; Project End 31-MAR-2003 Summary: "Glucose toxicity" accounts for insulin resistance in uncontrolled Type I diabetes (IDDM) and contributes to insulin resistance in Type II diabetes (NIDDM). Sustained hyperglycemia or hyperinsulinemia cause insulin resistance; glucose and insulin act synergistically in down- regulating insulin-stimulated glucose transport. A hypothesis to be tested in 3T3-Ll adipocytes is that glucose/insulin induced glucose transport desensitization reflects altered subcellular trafficking of the glucose transporter, GLUT4, which may involve impaired GLUT4 translocation and inappropriate association of GLUT4 containing vesicles (GCV) with the plasma membrane. Products of the hexosamine synthesis pathway (HNSP) have been implicated in glucose-induced insulin resistance; glutamine-fructose-6-P amidotransferase (GFAT) is the rate limiting enzyme and UDP-N-acetyl glucosamine (UDP-GlcNAc) the major product. The role of HNSP will be tested by examining whether conditions which increase or decrease flux via HNSP augment or mitigate, respectively, glucose induced insulin resistance. O-GlcNAcylation is a reversible process, involving O-glycosylation of proteins on Ser/Thr residues with monosaccharide GlcNAc. It usually involves phosphorylation sites and may be regulatory. Based on preliminary data in muscles of a mouse model of insulin resistance, over-expressing GLUTI in muscle, the hypothesis will be tested that increased flux via HNSP promotes O-GlcNAcylation of critical proteins involved in insulin- stimulated glucose transport. These may include GSV-associated proteins, possibly GLUT4 itself and/or proteins associated with GSV docking and fusion. Since adaptive regulation usually involves multiple sites, we will test the hypothesis that glucose-induced insulin resistance represents in part down-regulation of the insulin receptor (IR) signaling cascade, attempt to identify the major regulatory sites and critically assess the possible contribution of HNSP to the glucose effect. If warranted, the involvement of modulators of IR signal transduction, I.E. protein kinase C (PKC) isoforms, and candidate protein tyrosine phosphatases (PTP-ases: PTP-1B, SH-PTP2 and LAR) will be examined. GFAT activity is allosterically regulated by UDP-GlcNAc, and is modulated in vivo in muscle by the hormonal and metabolic milieu. The pre- and posttranslational regulation of GFAT expression will be studied in muscles of rodent models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: FETAL BRANCHED CHAIN AMINO ACID AND KETOACID METABOLISM Principal Investigator & Institution: Liechty, Edward A.; Professor; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 01-AUG-1987; Project End 31-MAY-2004 Summary: The regulation of fetal growth is coordinated by a complex interaction of substrate supply and endocrine signals of fetal and placental origin: insulin and insulin-

32

Insulin

like growth factor 1 are believed to have the major regulatory roles. We have been investigating the regulatory roles of these hormones in the ovine fetus, particularly their regulation of proteolysis and amino acid catabolism. We have found that the fetus is resistant to insulin's effect to suppress proteolysis, but insulin is potent inhibitor of amino acid catabolism. IGF-1 inhibits proteolysis by 30%, but has a lessor effect on acid catabolism. The hypothesis of the present proposal is that during brief elevations of insulin and IGF-1, the hormones act in distinct but synergistic manners to promote tissue accretion, insulin by promoting carbohydrate utilization and suppressing amino acid catabolism, and IGF-1 by suppression proteolysis. Insulin acts to reduce amino acid catabolism, directly affecting the activity state of enzymes responsible for amino acid catabolism. IGF-1 acts independent of insulin to decrease proteolysis by suppressing the ubiquitin proteolytic system in the fetus. However, as the length of time in the elevation of plasma IGF-1 progresses, stimulation of protein synthesis becomes predominant, and suppression of proteolysis decreases. Finally, we hypothesize that circulating fetal IGF-1 acts primarily on fetal tissues, but also has effects on placental tissues to alter metabolism and/or transport. These hypotheses will be investigated through three specific aims. 1. To verify that the branched chain dehydrogenase complex in the fetus is a) regulated by the phosphorylation/dephosphorylation; and b) that insulin and insulin-like growth factor act by regulation of the activity state of the complex. 2. To investigate the mechanisms by which IGF-1 inhibits fetal proteolysis. The ubiquitin system will be investigated. We hypothesize the IGF-1 inhibits the ubiquitin system at the gene transcription level, thereby inhibiting fetal proteolysis. 3. To investigate the transplacental flux rates of important fetal substrates during infusion of IGF-1 and/or insulin. 4. To compare and contrast the acute versus chronic effects of increased plasma IGF-1 on fetal growth and protein kinetics. Investigations will be carried out in the chronically catheterized fetal lamb. IGF-1 and insulin will be infused singly and in combination, with detailed analysis of fetal protein kinetics and placental substrate transfer rates determined. In addition, hormonal regulation of the branched chain ketoacid decarboxylase complex and the ubiquitin proteolytic will be examined in detail at the cellular level. These studies will result in important new information system regarding the mechanisms of fetal protein accretion, which will be important in evaluations of the potential for IGF-1 and/or insulin therapy for intrauterine growth restriction or inadequate postnatal growth in premature infants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPRESSION

GLUCOSE

REGULATION

OF

PANCREATIC

ISLET

GENE

Principal Investigator & Institution: Robertson, R Paul.; Scientific Director and Ceo; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-DEC-1985; Project End 31-MAR-2006 Summary: (provided by applicant) The overall goal of this proposal is to examine the hypothesis that the adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. The four specific aims are: Specific Aim #1: To determine whether intervention with antioxidants after establishment of hyperglycemia in ZDF rats is successful in decreasing plasma markers for oxidative stress, and, if so, also in decreasing plasma glucose levels and restoring islet PDX-1 and insulin mRNA, insulin content, and glucose-induced insulin secretion. We will also determine whether discontinuation of antioxidant treatment is followed by

Studies

33

reversion to the pretreatment level of hyperglycemia and defects in beta cell function. Specific Aim #2: To determine whether progression of type 2 diabetes mellitus in db/db mice is accompanied by disruption of the balance between reactive oxygen species and islet antioxidant enzyme gene expression, enzyme levels, and enzyme activity and defects in PDX-1 and insulin gene expression, and to determine whether db/db mice transgenically modified to overexpress intraislet antioxidant enzymes as a preventive measure are protected from glucose toxicity-induced progression of type 2 diabetes. Specific Aim #3: To determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations disrupts the intracellular balance between reactive oxygen species (ROS) and anti-oxidant enzyme gene expression, enzyme levels, and enzyme activity, thereby causing defective insulin gene expression and to determine whether in vitro overexpression of antioxidant enzymes islets prevents adverse effects of supraphysiologic glucose concentrations on PDX-1 and insulin gene expression, insulin content, and glucose-induced insulin secretion. Specific Aim #4: To ascertain whether measures of oxidative stress correlate positively with the level of hyperglycemia and negatively with residual beta cell function in type 2 diabetic patients; whether the intervention of improving glycemic control in type 2 diabetic patients leads to decreases in markers of oxidative stress and improvements in beta cell function; and whether interventional treatment with an antioxidant drug without changing current conventional drugs used for glycemic control diminishes hyperglycemia and improves beta cell function in poorly controlled type 2 diabetic patients. The methods used to achieve these specific aims will involve studies of insulin secretion, insulin content, PDX-1 and insulin mRNA levels, antioxidant enzyme levels and activity, and blood and islet markers for oxidative stress. We will conduct experiments using ZDF rats and antioxidant drugs, rat and human islets with adenoviral infection of cells to overexpress antioxidant enzymes, and db/db mice made transgenic to overexpress antioxidant enzymes, both singly and in combination. At the conclusion of these studies, we hope to have determined whether chronic oxidative stress is a mechanism of action for glucose toxicity in islets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GRB10 AS AN INSULIN RECEPTOR ADAPTER PROTEIN Principal Investigator & Institution: Smith, Robert J.; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2001; Project Start 01-FEB-1992; Project End 31-MAR-2003 Summary: (Adapted from applicant's abstract): The insulin and insulin-like growth factor I (IGF-1) signaling pathways are characterized by close homologies in hormone structure, receptor structure, and the signaling intermediates activated as a consequence of hormone binding. However, despite these marked similarities, insulin functions primarily as a metabolic regulatory hormone and IGF-I primarily as a growth factor. The long-term goals of this project are to define the molecular mechanisms that establish specificity in the insulin and IGF-I pathways, and extent of physiologically important interactions between insulin and the IGFS. Two-hybrid cloning studie during the previous grant period identified Grb10 as a novel protein that bind to the intracellular domain of activated insulin receptors but not IGF-1 receptors. This occurs through two receptor-binding sites in Grb10, an SH2 domain and a previously uncharacterized protein interaction motif. Grb10 co-precipitates with additional proteins besides the insulin receptor. The specific aims of this project are: (1) to investigate Grb10 function by introducing various constructs of this protein into insulin-responsive cell systems using recombinant adenovirus, (2) to identify proteins in addition to the insulin

34

Insulin

receptor that bind to Grb10 by both two-hybrid cloning and GST-Grb 10 fusion protein interaction methods, (3) to investigate the multiple isoform of Grb10 that have been identified, (4) to investigate the sites and functiona importance of Grb10 phosphorylation, and (5) to determine the structural basis for GrblO binding to the insulin receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATIC INSULIN GENE EXPRESSION IN IDDM Principal Investigator & Institution: Woo, Savio L.; Professor and Director; Center for Gene Therapy & Molecular Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 15-SEP-1998; Project End 31-JUL-2002 Summary: Insulin-dependent diabetes mellitus (IDDM) is characterized by a severe deficiency of insulin secondary to the autoimmune destruction of pancreatic beta cells. Current treatment for IDDM includes multiple daily insulin injections and specialized regimens of diet and exercise. Occasional lapses in patient compliance can result in acute episodes of ketoacidosis that can be fatal, and alternative long-term strategies such as islet cell transplantation or implantation of insulin infusion pumps are currently under active investigation. The liver is a key organ in maintaining glucose homeostasis in response to insulin and in ketogenesis during severe insulin deficiency. An adjuvant treatment for IDDM is hepatic insulin gene expression, whereby insulin is produced following transfer of the insulin gene into parenchymal cells of the liver. We have previously shown that the administration of a recombinant retroviral vector expressing the rat preproinsulin-1 cDNA to streptozotocin-induced diabetic rats can completely prevent ketoacidosis and normalize their fasting blood glucose levels. Further experiments performed with a recombinant retroviral vector expressing a form of the rat preproinsulin-1 cDNA engineered to allow its processing to mature insulin in hepatocytes have defined the therapeutic window that will prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia. The objectives of the current proposal are: 1) To obtain similar therapeutic results using non-invasive alternatives to the surgical partial hepatectomy that was necessary to achieve significant retrovirus-mediated transduction of hepatocytes in the previous studies; 2) To achieve some form of regulated insulin expression, so that insulin expression is induced under conditions of hyperglycemia and suppressed under conditions of hyperinsulinemia. Such regulation is not intended to restore the rapid physiological control of insulin secretion that normally occurs in response to changes in blood glucose levels, but rather to serve as a safeguard against prolonged periods of hyper- or hypoglycemia. Finally, using the naturally-occurring BB Worcester rat model of diabetes, the hypothesis that a recombinant retroviral vector incorporating these features of insulin expression and regulation can be used to prevent both the acute and chronic complications of IDDM will be rigorously tested. Successful conduct of the proposed research will lead to the development of a novel modality for adjuvant treatment of IDDM in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: HORMONAL AND NUTRITIONAL CONTROL OF ENZYME BIOSYNTHESIS Principal Investigator & Institution: Sul, Hei Sook; Professor; Nutritional Sciences; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 01-MAR-1985; Project End 31-MAR-2002

Studies

35

Summary: The long-term objective is to understand the molecular mechanisms underlying insulin-induced transcription of lipogenic genes. Insulin is the principal hormone that controls blood glucose. When circulating insulin is high there is an increase in fatty acid and fat synthesis in adipose tissue and liver; these processes are impaired when insulin is low and insulin restores the rates to normal. Diabetes is among the most common and serious metabolic diseases and understanding insulin action is of utmost importance. The goal of this research is to understand at a molecular level insulin induction of fatty acid synthase (FAS), the central lipogenic enzyme that catalyzes all reactions in the synthesis of palmitate from acetyl CoA and malonyl CoA. We previously found that insulin rapidly and markedly increases FAS gene transcription and recently defined insulin response sequence (IRS) at the proximal promoter region of the FAS gene and found upstream stimulatory factor (USF) binding to this sequence in vitro. The resent studies are to characterize the cis-trans system and signaling pathway for insulin- stimulated FAS transcription with the following specific aims: 1. To examine whether USF is involved in insulin regulation of the FAS insulin response complex. USF as an insulin response mediator will be established by correlating functional and bind activities, using in vitro mutagenesis of the IRS and by expressing dominant-negative USFs. GAL4-USF fusion will also be used to assess the role of USF as an insulin response mediator. 2. To isolate and clone other potential component of the FAS insulin response complex. If USF is proven to be a component of insulin response complex, a novel heterodimerization partner of the USF will be cloned by yeast interaction trap or by in vitro protein-protein interaction. If USF is proven not to be involved in insulin regulation, the putative IRS binding protein will be purified and/or cloned. 3. To explore signaling pathway by examining effects of specific inhibitors and dominant negative forms of signal molecules on insulin activated FAS promoter-luciferase activity. We will also examine whether USF or other protein component undergo phosphorylation- dephosphorylation. 4. To further examine the FAS promoter sequence in vivo. The first 2.1 kb of the 5'-flanking sequence of the FAS gene is sufficient for tissue-specific and hormonally regulated expression in transgenic mice. The sequence for insulin regulation will be further defined by transgenic mice that contain 5'deletion FAS-CAT constructs to demonstrate and confirm its role in vivo and by genomic footprinting by ligation-mediated PCR to demonstrate in vivo protein-DNA interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOTHALAMIC PEPTIDES, FOOD INTAKE, AND DIABETES Principal Investigator & Institution: Schwartz, Michael W.; Professor and Head,; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2003; Project Start 01-SEP-1994; Project End 31-AUG-2007 Summary: (provided by applicant): Uncontrolled diabetes mellitis (uDM) is a unique and well-defined rodent model for delineating the neuroendocrine mechanisms that control food intake. The hypothesis that neuronal systems in the arcuate nucleus (ARC) of the hypothalamus are regulated by hormones such as insulin and leptin that circulate in proportion to body fat mass has received strong support from studies using this model. Specifically, ARC neurons that promote increased food intake, such as the NPY/AgRP neuron, are activated by the effect of uDM to lower insulin and leptin levels. Similarly, ARC POMC neurons, which reduce food intake, are inhibited by these hormonal responses. Several observations suggest that the effect of uDM to increase food intake, known as diabetic hyperphagia, results at least in part from these ARC neuronal responses. The intracellular mechanism whereby insulin and leptin regulate

36

Insulin

ARC neurons is hypothesized to involve activation of the insulin receptor substratephosphatidylinositial-3-OH kinase (IRS-PI3K) pathway. A key hypothesis of the current proposal is that reduced PI3K signaling in ARC neurons results from deficient signaling by insulin and leptin and plays a critical role in their response to uDM. A related hypothesis is that reduced signaling via PI3K in ARC neurons mediates not only food intake stimulation, but also contributes to hyperglycemia by causing insulin resistance in peripheral tissues. Finally, new data from the investigator's laboratory suggests that the orexigenic gastric hormone ghrelin may also contribute to the hypothalamic response to uDM. Studies are proposed to 1) identify ARC neurons in which PI3K is activated by insulin treatment of uDM; 2) identify hypothalamic, behavioral (e.g., diabetic hyperphagia) and metabolic responses to uDM that are dependent on reduced PI3K signaling in the ARC; 3) determine whether the ability of insulin to reverse hypothalamic, behavioral or metabolic responses to uDM requires hypothalamic PI3K signaling; and 4) determine the contribution of elevated plasma ghrelin levels to manifestations of uDM. This work will fundamentally advance our understanding of the neuroendocrine control of food intake and glucose metabolism, and has the potential to identify new, neuronal factors that influence insulin requirements in patients with diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPAIRED BETA CELL GENE EXPRESSION IN A MODEL OF NIDDM Principal Investigator & Institution: Griffen, Steven C.; Assistant Professor; Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: NIDDM results from at least two defects, namely reduced insulin secretion from pancreatic beta-cell and resistance to insulin action. At least 25% of the nondiabetic population has insulin resistance in the diabetic range. What distinguishes those who eventually develop diabetes if the failure to overcome the insulin resistance by increasing insulin production and secretion. The nature of the impaired beta-cell function in the majority of cases of NIDDM remains unknown. The Zucker fatty rat has severe insulin resistance and hyperlipemia, but does not develop diabetes. A sub-line derived from these rats, the Zucker diabetic fatty (ZDF) rat has similar insulin resistance but the males develop diabetes due to impaired insulin secretion and in this regard are similar to most humans with NIDDM. The proposed studies will investigate the nature of the beta-cell defect in the ZDF rat model of NIDDM. Preliminary experiments have demonstrated a defect in insulin gene transcription in these animals. The activity of key elements in the insulin promoter will be tested in transfected primary ZDF rat betacells. Extracts of nuclear proteins will be screened for alterations in the quantities of transcription factors which are known to be key regulators of the insulin promoter. The effects of free fatty acids on gene expression in the ZDF beta-cell will also be determined. These studies will define the beta-cell defect in the ZDF rat and may help give insight into the defects in insulin production and secretion seen in NIDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: IN VIVO NOD EVALUATION OF A PATHOGENIC INSULIN PEPTIDE Principal Investigator & Institution: Eisenbarth, George S.; Executive Director; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508

Studies

37

Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-MAR-2006 Summary: (provided by applicant): During the past 2.5 years with support from the current grant we have begun the breeding to produce congenic strains with the insulin 1 (N4 generation) and insulin 2 knockouts (N7generation) on the NOD background, and utilizing the speed congenic methodology have fixed NOD diabetes susceptibility regions. Constructs for the production of altered insulin sequences with retained biologic activity have been produced, and transgenic with germline transmission demonstuted (In collaboration with John Elliott). Our long term goal is to combine the insulin 1 and 2 knockouts with transgenes encoding altered insulin B:9-23 sequences in the same NOD strain and evaluate whether the B:9-23 native sequence is essential for the development of type 1 diabetes in the NOD mouse. Over the past two years we have continued our studies of autoimmunity directed at insulin with findings that include: 1. NOD T cell clones recognizing insulin peptide B:9-23 recognize two different overlapping insulin peptides, B:9-16 or B:13-23. 2. With a modified fluid phase radioassay insulin autoantibodies are readily detected in NOD mice and early expression of such autoantibodies correlate with early development of diabetes. 3. The insulin peptide B:9-23, specifically (no other insulin or proinsulin peptide tested) when administered to NOD mice induces insulin autoantibodies in an MHC restricted fashion (I-Ag7) or I-Ad) recognizing intact insulin concomitant with protection from diabetes. 4. The B:9-23 peptide, as well as B:13-23 when administered to normal Balb/C mice but not C57/B16 mice induces autoantibodies reacting with intact insulin that cannot be absorbed with the peptides but can be absorbed with "mouse" insulin. 5. Three different anti-islet transgenic mice (BDC2.5, Santamaria 4.1 and 8.3) all produce anti-insulin autoantibodies. 6. Insulitis can be induced in Balb/c mice by combining B:9-23 with poly1C, and diabetes can be induced in islet B7-1, H-2d/H-2b mice given B:19.-23 and poly-1C. During this same time period Wong and coworkers have characterized a CDS clone reacting with insulin peptide B:15-23 and have provided us with the clone and protocols for tetramer analysis for such T cells. We propose to: 1. Analyze congenic strains of NOD mice carrying the insulin 1 and 2 knockouts relative to expression of insulin autoantibodies, insulin peptide reactive T cells, and development of diabetes. 2. Produce strains of transgenic NOD mice with altered sequences of the B:9-23 insulin sequence 3. Evaluate NOD mice lacking native insulin 1 and 2 but with the transgene altered insulin for expression of insulin autoantibodies, insulin peptide reactive T cells, and development of diabetes. 4. Evaluate insulin peptide B:9-23 and altered peptide ligand for disease prevention in native NOD mice and mice with altered sequence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLAMMATION AND INSULIN RESISTANCE IN PAD Principal Investigator & Institution: Creager, Mark A.; Associate Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Patients with peripheral arterial disease (PAD) frequently have functional limitations and symptoms of claudication that impact adversely on their quality of life. Many progress to critical limb ischemia requiring revascularization. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in vascular function and insulin resistance interferes with skeletal muscle metabolism. As such, inflammation and insulin resistance provide attractive targets for therapy that could potentially ameliorate the development of symptomatic PAD or improve the function and clinical

38

Insulin

outcomes of patients with PAD. Accordingly, the applicants propose three specific aims to determine whether inflammation and insulin resistance contribute to the functional and clinical consequences of PAD. First, a prospective, nested, case-control evaluation will be performed to test the hypothesis that baseline plasma levels of inflammatory cytokines (e.g. interleukin (IL)-4, IL-6, IL-18, macrophage inhibiting cytokine-1, CD 40 ligand) among healthy men are associated with the development of future symptomatic PAD. Second, to test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function, plasma markers of inflammation and insulin resistance, endothelium-dependent and independent vasodilation (by vascular ultrasonography) and skeletal muscle glucose utilization (by [18F] FDG positron emission tomography) will be measured before and after 12 weeks of treatment with rosiglitazone, atorvastatin or placebo in a 2x2 factorial design protocol. Third, to test the hypothesis that inflammation and insulin resistance are associated with the incidence and progression of vein graft disease in patients undergoing lower extremity vein bypass, functional and morphologic changes in vein grafts (measured by ultrasound and magnetic resonance imaging) will be assessed and related to inflammation and insulin resistance and to a composite clinical outcome of graft occlusion, re-intervention or major amputation. It is anticipated that the findings from this investigation will uncover novel pathophysiologic mechanisms and foster a new paradigm for the treatment of PAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLUENCE ADOLESCENCE

OF

INSULIN

ON

BP

CHANGE

DURING

Principal Investigator & Institution: Sinaiko, Alan R.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 05-MAY-1995; Project End 31-MAY-2004 Summary: (Adapted from the Investigator's Abstract) This research application is a continuation of a project initiated in 1995 to study insulin resistance in children. The primary objectives are (1) to define the relation of insulin resistance (defined by the euglycemic insulin clamp) during childhood and adolescence to the development of the insulin resistance syndrome (i.e., hypertension, dyslipidemia, obesity, and insulin resistance) in young adulthood; and (2) to define the relation of the insulin resistance syndrome within families and the importance of genetics to that relation. The original cohort consists of 357 children who have had two euglycemic insulin clamp studies (at mean ages 13 and 15 years). The specific aims are: to (1) repeat anthropometric and blood pressure measurements at mean ages 18, 19, and 20 and obtain insulin clamps, lipid levels, echocardiograms, and DEXA at mean age 21 in the children; and (2) obtain the measurements, blood and DNA samples, echocardiogram, and insulin clamp in the parents and siblings of the children. Statistical genetics methods will be used to estimate heritability and genetic correlations among the insulin resistance syndrome traits. These data will address the hypotheses that 1) insulin resistance in childhood will predict insulin resistance and cardiovascular risk factors in young adulthood; 2) insulin resistance in parents will be associated with insulin resistance and cardiovascular risk factors in their children; 3) in fat children, BMI and insulin resistance at mean age 13 will predict cardiovascular risk, but in thin children only insulin resistance will be a similar predictor; 4) insulin resistance has significant heritability; and 5) there are significant genetic correlations between insulin resistance and the insulin resistance traits. It is anticipated that at least 300 of the original cohort of 357 who have had two

Studies

39

euglycemic insulin clamps will complete the five years of this continuation. The investigators state that the significance of this project lies in its potential to define the factors influencing development of the insulin resistance syndrome and provide the basic clinical data required to begin to study genetic patterns of cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INOSITOL SIGNALING IN C. ELEGANS SENESCENCE AND DIAPAUSE Principal Investigator & Institution: Ruvkun, Gary B.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-AUG-2006 Summary: (APPLICANT'S ABSTRACT): An insulin signaling pathway couples feeding and nutritional status in mammals to metabolism in most tissues. An insulin-like signaling pathway regulates longevity and metabolism in C. elegans. This is reminiscent and may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Our genetic analysis has also revealed that the signal transduction components and transcriptional outputs of C. elegans insulin-like signaling pathway. Mammalian orthologs of many of these genes have been identified. Thus the genetic components of the C. elegans insulin signaling pathway may be key components of a mammalian longevity determining pathway. While many points of congruence have been identified, we know from genetic epistasis experiments that there are missing components. We will identify these components by second generation genetics, using the mutants identified in the first round of genetics as tools in the genetics of this round. We will also explore the connection between reproductive longevity and organismal longevity by genetically analyzing the regulation of reproductive senescence in C. elegans. We have shown that C. elegans has a large family of insulin-like hormones and that human insulin will function in C. elegans. Our genetics have revealed that not all responses to C. elegans as well as human insulin are mediated by the canonical insulin response receptors. We will explore the novel insulin response pathway by genetic analysis. We will determine the molecular identity of the worm genes revealed by the extensive genetic analysis proposed in the grant, search for human homologues of those genes, and test whether these human proteins in fact can function in the C. elegans insulin-like signaling pathway, that is, are functional homologues. In addition to their possible roles in longevity control, the insulin signaling genes we have identified by C. elegans genetics may reveal components of insulin signaling in mammals that are important for the understanding and eventual treatment of diabetes. Diabetes is a common disease that affects the production or response to insulin, causing devastating metabolic dysregulations. The molecular basis of the defective insulin response in the adult onset or type II diabetes is unknown. It is clear that it is at least in part a genetic disease. Saturation genetic analysis of the homologous C. elegans metabolic control pathway has revealed genes that act downstream of the insulin-like receptor as well as other neuroendocrine signals that converge with insulin. The products of the genes we have identified may be targets for pharmaceutical development of diabetes therapies Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INSULIN ACTION IN MUSCLE & FAT CELL Principal Investigator & Institution: Lawrence, John C.; Professor; Pharmacology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904

40

Insulin

Timing: Fiscal Year 2001; Project Start 01-APR-1981; Project End 31-MAR-2006 Summary: Insulin lowers blood glucose by stimulating glucose uptake and storage in various target tissues, the most important being liver, skeletal muscle, and fat. The failure to respond appropriately to insulin results in a rise in blood sugar. Type II diabetes mellitus develops if beta cells become unable to release enough insulin to compensate for the insulin resistance. Determining the processes involved in the normal response to insulin will be essential for understanding insulin resistance, and the overall objective of this project is to define mechanisms involved in the actions of insulin in skeletal muscle and fat cells. Initial aims are to investigate the stimulation of glycogen synthesis by insulin. This effect is of particular importance in the control of blood glucose levels, as most of the glucose taken up following a meal is deposited as glycogen in skeletal muscle. Experiments in Aim 1 are proposed to investigate both the mechanism through which insulin activates glycogen synthase (GS), the enzyme that synthesizes glycogen from uridine diphosphoglucose (UDPG), and the importance of increasing GS activity in the stimulation of glycogen synthesis. Treating rats with insulin results in a marked decrease in muscle UDPG, implying that the activity of UDPG pyrophosphorylase (PPL) may limit the rate of glycogen synthesis. Objectives of Aim 2 are to determine whether UDPG PPL is subject to hormonal and/or metabolic control, and to investigate the potential limiting role of UDPG PPL in glycogen synthesis in rodent and human muscles. In the last two Aims we will investigate new targets of insulin action. We have recently discovered an adipocyte protein, designated betaip140, which is phosphorylated in response to insulin and coimmunoprecipitates with the beta isoform of protein kinase B (PKB). By purifying betaip140 and sequencing peptides by tandem mass spectrometry, we have shown that betaip140 is the product of the Kiaa0188 gene, recently identified by genetic fine mapping as a candidate gene for the fld mouse phenotype. Mice homozygous for the fld gene exhibit insulin resistance, glucose intolerance, and markedly diminished adipose tissue mass. Aim 3 is to investigate the potential interactions between betaip140 and PKBbeta, to define the mechanisms controlling betaip140 phosphorylation, and to determine the role of betaip140 in insulin action. Many other proteins that are phosphorylated in response to insulin can be detected, but have not been identified. This represents a serious gap in our understanding of insulin action, since at least some of the proteins are likely to represent downstream targets that are involved in the important metabolic responses to insulin. The objective of Aim 4 is to identify these new targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN AND THE POLYCYSTIC OVARY SYNDROMEN Principal Investigator & Institution: Nestler, John E.; Professor and Chairman; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31-JUL-2005 Summary: The polysystic ovary syndrome (PCOS) is a poorly understood disorder that affects approximately 6-10 percent of women of reproductive age. PCOS is characterized by hyperandrogenism and chronic anovulation, and is the leading cause of female infertility in the United States. Women with PCOS are also at high risk for developing type 2 diabetes, presumably due to the insulin resistance that accompanies the syndrome. Our long-term goal is to elucidate the relationship between insulin resistance and PCOS, especially as it relates to hyperandrogenism. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action and a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in individuals with impaired glucose tolerance or type 2 diabetes. Our

Studies

41

studies indicate that D-chiro-inositol (DCI) administration improves glucose intolerance while reducing circulating insulin in women with PCOS, and is also associated with decreases in serum androgens and improved ovulatory function. In addition, our in vitro studies in human thecal cell cultures suggest that the IPG signaling system plays a role in transducing insulin's stimulation of ovarian androgen biosynthesis. These studies have led us to focus our short- term goals on an assessment of the role of the IPG signaling system in PCOS, and pursue a unifying hypothesis to explain the above experimental observations. Our hypothesis is that women with PCOS are DCI deficient, perhaps related to an intracellular defect in the conversion of myo-inositol (MYO) to DCI. This results in a decrease in a DCI-containing IPG mediator (DCI-IPG) and an increase in a MYO-containing IPG mediator (MYO-IPG) bound to the outer leaflet of the cell membrane. We further propose that the resulting deficient insulin-mediated release of DCI-IPG contributes to insulin resistance in PCOS, whereas the simultaneous hyperinsulinemia mediated increased release of MYO-IPG at the level of the ovary acts to stimulate ovarian androgen biosynthesis. If our proposed studies confirm a role for IPG's in insulin resistance and hyperandrogenism of PCOS, they will substantially enhance our understanding of the disorder's pathogenesis and are likely to provide insights into novel treatment strategies directed specifically at the IPG system and normalization of its function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN MEDIATED GLUCOSE TRANSPORT DISRUPT BY ETHANOL Principal Investigator & Institution: Nagy, Laura E.; Associate Professor; Nutrition; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: (Adapted from the investigator's abstract). Epidemiological studies have identified alcohol consumption as an independent risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM). Moreover, both short and long-term ethanol consumption result in glucose intolerance in humans and rats. However, the mechanism(s) for this disruption of glucose homeostasis by ethanol is not well understood. Since adipose and skeletal muscle are major sites for both insulin action and glucose disposal, the applicants have investigated the effects of ethanol on insulinmediated control of glucose transport in adipocytes and skeletal muscle from rats. Ethanol feeding to rats for four weeks decreased insulin-stimulated glucose uptake in adipocytes and soleus, a red oxidative muscle, but had no effect on uptake in the epitrochlearis, a white glycolytic muscle. Decreased uptake in the adipocyte was associated with an impairment in translocation of GLUT4 from intracellular vesicles to the plasma membrane. Total GLUT4 protein was also reduced after ethanol feeding; as in other model systems, decreased GLUT4 was associated with an increase in G alpha s and cAMP production in the adipocyte. The major goals of this proposal will be to determine whether ethanol impairs insulin-stimulated glucose uptake in red, oxidative muscle and adipocytes by: (1) disrupting insulin receptor mediated signal transduction and/or (2) impairing the ability of GLUT4 vesicles to dock and fuse with the plasma membrane. The effects of ethanol on early events in insulin signalling (insulin receptor substrate-1 phosphorylation and activation of phosphotidylinositol-3-kinase) which lead to translocation of GLUT4 will be measured. The applicants will also investigate the effects of ethanol on the intracellular distribution of GLUT4 protein after insulin stimulation, as well as the distribution of vesicular proteins involved in GLUT4 vesicle trafficking. Investigation of the mechanisms for ethanol-induced insulin resistance is

42

Insulin

critical for understanding the interaction between alcohol consumption and the development of NIDDM. Such an understanding will foster the development of strategies to either prevent or reverse the long-term effects of ethanol on glucose homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN PRODUCING VECTORS FOR GENE THERAPY OF DIABETES Principal Investigator & Institution: Ripps, Michael E.; Laboratory Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-DEC-2003 Summary: Strong impetus exists for developing improved modes of insulin delivery for the treatment of diabetes mellitus. The insertion of appropriately regulated insulin genes into non-islet tissues is a potential strategy for the treatment of type I diabetes, in which islet cells are destroyed by autoimmune mechanism. The objective of the proposed project is to explore an approach to gene therapy for diabetes for engineering glucose regulated insulin production in extra-pancreatic sites. Our approach will be to target insulin expression to hepatocytes and intestinal epithelial cells in vivo using an insulin gene construct driven by the liver-type pyruvate kinase (L-PK) promoter. Since L-PK promoter activity is stimulated by glucose and blocked by glucagon and cyclic AMP, we expect that insulin synthesis and secretion will increase after a carbohydrate meal, and that possible over-production of insulin leading to severe hypoglycemia may be prevented by the cAMP-mediated actions of glucagon and epinephrine. Since the LPK promoter requires permissive amounts of insulin to be active, a second gene construct expressing insulin from a modified metallothionein promoter will be transferred along with the L-PK/insulin gene to provide a basal level of insulin. Double gene cassettes will be packaged into adeno-associated virus vectors and transferred in vivo to mice rendered diabetic by ablation of pancreatic beta cells using the drug streptozotocin. The time course of L-PK/insulin gene activation and repression will be determine after glucose loads and during insulin-induced hypoglycemia. Possible amelioration of the diabetic state will be assessed by oral glucose tolerance tests and measurement of glycohemoglobin levels. New initiatives in gene therapy will undoubtedly require the development of control systems to achieve the desired expression level for varying physiological or therapeutic circumstances. This project will assess a new therapeutic approach to diabetes and may also serve as a model for future attempts to engineer control systems for gene transfer. Furthermore, the Research Center Award will enhance my development as a physician-scientist and allow me to reach my long-term goal of an independent research career in academic medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INSULIN RECEPTOR SIGNALING IN THE RETINA Principal Investigator & Institution: Rajala, Raju Vs; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 16-SEP-2002; Project End 31-AUG-2007 Summary: Insulin, a peptide hormone binds its cognate cell surface receptors to activate a coordinated biochemicalsignaling network and induce intracellular events. The retina is an integral part of the central nervous system and is known to contain insulin receptors, although their function is not known. Recently, we have reported that the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) interacts directly with the

Studies

43

insulin receptor-beta subunit (IRb) in retinal rod outer segments (ROS), which leads to activation of the PI3K enzyme. This interaction can be achieved either by light in vivo or through tyrosine phosphorylation of insulin receptor in vitro. This work linking PI3K activation through tyrosine phosphorylation of the insulin receptor in ROS now provides physiological relevance for the presence of these receptors in the retina. The mechanism of light activation of the insulin receptor and the functional consequences are unknown and therefore need to be investigated. In this proposal, four specific aims are outlined that will provide fundamental information on insulin receptors in the retina. 1) To test the hypothesis that photopigments and the visual transduction cascade mediate the light-stimulated tyrosine phosphorylation of the IRb. 2) To elucidate the mechanism of light-stimulated tyrosine phosphorylation of the IRb. 3) To determine the role of insulin binding protein Grbl0 in the regulation of the IRb. 4) To employ transgenic frog approach to study the movement of proteins in retina. These studies are being undertaken with the ultimate goal of understanding the biochemical mechanism of light signaling through the insulin receptor and the downstream physiological consequences. In this application, we propose to study the mechanism of light activation of insulin receptor employing various transgenic and knockout mouse models, biochemical, and molecular and immunological experiments. Our long-term goal is to understand the role of insulin receptors in the retina and elucidate the intracellular signaling pathways they generate. The biological implication extends to the cause and treatment of a number of retinal degenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN REGULATED MEMBRANE TRAFFICKING Principal Investigator & Institution: Mcgraw, Timothy E.; Associate Professor; Biochemistry; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 01-SEP-1997; Project End 31-DEC-2007 Summary: (provided by applicant): Insulin-stimulated redistribution of the GLUT4 glucose transporter from intracellular compartments to the surface of fat and muscle cells is the major mechanism for regulating postprandial glucose disposal and storage. This translocation is defective in Type II diabetes, although the molecular defect(s) that cause insensitivity to insulin is not known. It is important to understand both the mechanisms responsible for the basal state intracellular retention of GLUT4 and for the insulin-induced translocation to the surface. In this renewal application we continue our studies of insulin-regulated trafficking in 3T3-L1 adipocytes. The long-term objective is to understand this specialized trafficking pathway at a molecular level. In this project we will exploit the technical advantages of 2 reporter molecules that we have developed: a GLUT4-GFP construct and a chimera between IRAP and the transferrin receptor (vpTR). In Aim 1 of this application we will test a two-step insulin-regulated retention model of GLUT4 trafficking using biochemical and optical microscopy methods. The dynamic relationship between the insulin-regulated and general endosomal pathways will be defined using an HRP-mediate fluorescence quenching protocol. The concepts developed in aim 1 will be used in the other aims to further define the molecular mechanism of insulin-regulated trafficking. In aim 2 we will use dominant-inhibitors to determine whether proteins that regulate traffic from endosomes to the cell surface also function along the insulin-regulated pathway. In this aim we will also investigate the machinery that sorts GLUT4 from endosomes by determining whether the LL/acidic cluster motif that targets proteins to an insulin-regulated pathway in fibroblasts also functions in adipocytes. In aim 3 we will use the two-step insulin-regulated retention model as a conceptual framework for studies of how

44

Insulin

effectors of insulin-signal transduction recruit GLUT4 to the cell surface. The information derived from the studies of aims 1 and 2 is critical for understanding how the downstream effectors of the insulin receptor function to induce translocation of GLUT4. In aim 4 we will identify the proteins of the insulin-regulated pathway in adipocytes using the HRP-mediated compartment density shift method. A long-term objective is to determine the roles that these proteins play in insulin-regulated trafficking in adipocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN REGULATION OF CELL NUTRITION Principal Investigator & Institution: Kandror, Konstantin V.; Associate Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 28-FEB-1997; Project End 31-DEC-2002 Summary: (Adapted from Applicant's Abstract): Insulin stimulates glucose uptake in its target tissues (fat, heart, and skeletal muscle) mainly or entirely via translocation of glucose transporting activity from an intracellular pool to the cell surface. The protein responsible for the insulin-sensitive glucose transport, GLUT4, has been identified and cloned. The mechanism of the translocation process remains unknown. It is crucially important to find an answer to this question, because it will explain the fundamental principles of insulin action, and, in addition, will shed light on the molecular bases of insulin resistance in diabetes mellitus. To approach this problem, we started with characterization of the intracellular GLUT4-containing membrane compartment (vesicles) in basal and in insulin-treated rat adipocytes. We have shown that, besides GLUT4, this compartment incorporates the IGF-II/Man-6-P receptor, the transferrin receptor, the novel aminopeptidase gpl60 and a number of minor components. Thus, several proteins which (may) participate in cellular nutrition and metabolism are colocalized in the same intracellular membrane vesicles. All these proteins recycle between GLUT4-vesicles and their functional site, the plasma membrane, in an insulin dependent fashion. Their hormone-sensitive recruitment to the cell surface represents the major mechanism hat regulates intracellular uptake of glucose, iron, and other metabolites. The question arises of whether insulin stimulates translocation of the whole pre-existing compartment ("GLUT4-vesicles"), or different component proteins of GLUT4-vesicles recycle separately. In the last case, insulin is likely to cause formation of new transport vesicles which deliver their individual cargo to the cell surface via unidentified pathways. To discriminate between these two possibilities is the first major goal of the project. Besides the cell surface translocation of GLUT4 and co-localized proteins, insulin administration induces other major changes in adipocyte vesicular traffic. For example, it stimulates fluid-phase endocytosis, internalization of insulin receptors and, likely, lysosomal targeting of the endocytosed ligands. Thus, the second major goal is to provide a comparative study of different trafficking events in order to determine their common biochemical requirements as well as possible differences. Eventually, this work will provide us with a detailed picture of intracellular protein traffic in adipocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INSULIN RESISTANCE /DIET OF HISPANIC WOMEN W/ BREAST CAN Principal Investigator & Institution: Duarte-Gardea, Maria O.; University of Texas El Paso El Paso, Tx 79968

Studies

45

Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Background: Breast cancer is the most common cancer among women. A relationship has been hypothesized between insulin resistance and breast cancer. To our knowledge, no study has investigated the relationship among insulin resistance, energy and fat intake, and breast cancer in Hispanic women. The purpose of this project is to test the hypothesis that fasting insulin and other markers of insulin resistance, along with energy intake and dietary fat, will be significantly higher among Hispanic women diagnosed with breast cancer compared to those with no indication of cancer. Specific aims: Our aims are to compare the following characteristics among women with and without breast cancer: Aim 1) markers of insulin resistance and Aim 2) total energy and total fat intake. Aims 3) demographic, anthropometric, and reproductive, and Aim 4) lifestyle and dietary factors and their association with diagnosis of breast cancer. Design/Methods: A prospective case-control study of Hispanic women attending the University Breast Care Center at Texas Tech University Health Sciences Center at El Paso for routine breast examination will be conducted. Markers of insulin resistance including obesity, waist/hip ratio, blood pressure, acanthosis nigricans, fasting insulin, fasting glucose, and lipid profile will be performed in four hundred eligible participants. Subjects will complete a three-day food record to determine total energy and fat intake. Case and control groups will be formulated once the data are collected and after mammogram and pathology reports have been filed. The case group includes 100 subjects with breast cancer. Three controls (matched by age +/5 years) and menopausal status) for each case will be located from the pool of total participants. We will perform correlation and factor analyses to identify variables and/or factors which would best represent each of the four classes of independent variables as outlined in the specific aims section. We will then use logistic regression analysis to examine the relationship between the categorical response (diagnosed with and without breast cancer) with the set of independent variables identified above. The proposed work will advance the understanding of the associations of insulin resistance, diet and breast cancer in Hispanic women. Individual risk factors (anthropometric, health, reproductive, lifestyle and dietary) may be identified. There is a need for research that focuses on a comprehensive approach to insulin resistance, dietary lifestyle choices, and breast cancer and that emphasizes a fat-caloric intake-insulin resistance linkage. Such information is critical for the design of health education interventions that seek the adoption of healthy lifestyle in low income Hispanic population through community-based culturally relevant and tailored prevention programs, and public policy recommendations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND ADENOMAS OF THE COLORECTUM Principal Investigator & Institution: Byers, Tim E.; Professor of Preventive Medicine; Preventive Med and Biometrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: There is considerable evidence that insulin and/or insulin-like growth factors (IGFs) can increase risk of colorectal neoplasia. Epidemiologic risk factors for colorectal neoplasia are similar to those for insulin resistance syndromes, and prospective studies have shown both diabetes and higher levels of IGF-1 to be associated with colorectal cancer risk. No previous studies have included direct measures of insulin resistance, nor have any included complete ascertainment of colorectal neoplasia by direct examination of the entire colorectum. This study will

46

Insulin

assess the relationship between insulin resistance and colorectal neoplasia by taking advantage of a unique opportunity to examine a multi-ethnic cohort on whom prior measures of insulin sensitivity have been made. The Insulin Resistance and Atherosclerosis Study (IRAS) is a cohort study supported by the National Heart Lung and Blood Institute. IRAS examined 1628 people of average age 55 in 1991-1994 for atherosclerosis risk factors. The cohort, assembled in four clinical centers (Alamosa, Co., Los Angeles, Oakland, and San Antonio) was established to be multi-ethnic (34 percent Hispanic, 28 percent African American, and 38 percent non-Hispanic white), bi-gender, and varied in diabetes risk. In 1998-1 999 over 85 percent of the surviving cohort was reexamined. Both of the examinations have included measures of self-reported risk factors for atherosclerosis (diet, physical activity, tobacco use, family history) as well as anthropometry and, most importantly, oral glucose tolerance testing and frequentlysampled intravenous glucose tolerance tests (FSIGT). The FSIGT is a sensitive and specific measure of insulin resistance. All surviving cohort members (estimated 1518) will be invited to have a screening colonoscopy. Feasibility data indicate that 1000 will agree to have a colonoscopic exam, among whom we estimate 240 (range 206-274) will have adenomas. Mucosal biopsies will be taken from the cecum and rectum of all subjects, and all adenomas will be removed and examined for histologic features, Ki-ras mutations, proliferation, and apoptosis. Serum samples will be assayed for insulin, IGF1, IGFBPI, and IGFBP3 levels for all cohort members at both the time of colonoscopy, as well as at the time of two earlier examinations (199 1-4 and 1998-9) using stored serum samples. This study offers the advantage of the availability of prospective measures of glucose tolerance, insulin resistance, measurements of most colorectal neoplasia risk factors, and the availability of stored blood samples from a multi-ethnic and bi-gender cohort. Complete colorectal visualization of this entire cohort will enable unbiased estimates of colorectal neoplasia risk related to these factors. This study therefore offers a time-efficient and a cost-efficient method to test the hypothesis that colorectal neoplasia risk is increased substantially by factors related to insulin resistance, and to examine the biologic mechanisms whereby that risk is increased. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND VASCULAR DYSFUNCTION Principal Investigator & Institution: Raji, Annaswamy; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-DEC-2006 Summary: (provided by applicant) Epidemiological studies have shown that Asian Indians (AI) are insulin resistant (IR) and at risk for diabetes and coronary artery disease (CAD) when compared to Caucasians (C) of northern European ancestry. The increased risk of CAD in AI is not explained by the traditional risk factors like hypertension and lipid abnormalities suggesting that other factors play a role. A preliminary study by our group demonstrated that compared to C matched for body mass index (BMI) and age, AI were more IR and had altered body fat distribution. Recently there has been considerable interest in the role of insulin resistance in the pathogenesis of other physiological disorders, including endothelial dysfunction. Independent data suggests that IR states like obesity, type 2 diabetes and as well as young normoglycemic IR first degree relatives of diabetics have endothelial dysfunction. Based on these data, this project has its primary goal to test the hypothesis that healthy AI have IR, altered body fat distribution and endothelial dysfunction compared to C matched for age and BMI. We also hypothesize that Al have greater endothelial dysfunction compared to C with similar degrees of insulin resistance. The

Studies

47

secondary goal is to determine whether insulin sensitizers can improve IR and endothelial dysfunction in AI compared to C. We hypothesize that reversing insulin resistance using insulin sensitizers will correct endothelial dysfunction to a lesser degree in AI when compared to C with comparable insulin resistance. Healthy AI, C, and first degree relatives of Caucasian diabetics matched for BMI and age will undergo euglycemic hyperinsulinemic clamp to assess IR, brachial artery ultrasound to asses endothelial function in the basal and insulin stimulated states, CT scan to measure abdominal fat. It is anticipated that AI will be IR and have decreased endothelium dependent vasodilation in the basal and insulin stimulated states. AI will have greater degree of endothelial dysfunction compared to C with similar degrees of IR. The ability of the insulin sensitizers to improve IR and endothelial function will be examined in both AI and C. Subjects will be placed on pioglitazone for 16 weeks and will undergo all the tests done for the initial study. It is anticipated that there will be a substantial improvement of IR, endothelial function, and body fat distribution in Al compared to C matched for age and BMI. When compared to C with similar IR, we expect that AI will have lesser degree of improvement of their endothelial function, reflecting the presence of residual vascular dysfunction that contributes to their excess risk of CAD. There may be a substantial benefit to understand the underlying mechanism of IR and endothelial dysfunction in AI. This will enable us to initiate specific therapy to prevent diabetes and CAD in this ethnic group. Expertise and teaching from my mentors and a rich research environment at the Brigham & Women's Hospital will enable me to become an independent physician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE IN ADOLESCENTS AT HIGH RISK FOR PCOS Principal Investigator & Institution: Geller, David H.; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The applicant previously focused his research on molecular aspects of steroid hormone biosynthesis. He recently assumed a position as Assistant Professor of Pediatrics in the UCLA School of Medicine. To further his career, as an independent investigator, he has established relationships with experts in the fields of ovarian physiology, insulin signaling, sensitivity and secretion. Under their mentored supervision, the candidate will initiate studies to address the childhood origins of the polycystic ovary syndrome (PCOS). PCOS is a heterogeneous clinical entity characterized by the post-pubertal onset of menstrual irregularities and excessive production of male hormones. PCOS is the most common endocrine disorder of women of reproductive age, affecting 5-10% of women worldwide. Insulin resistance is a necessary antecedent of both type 2 diabetes mellitus (T2DM) and the hormonal imbalances characteristic of PCOS. As insulin resistance is a transient physiologic phenomenon of normal pubertal maturation, the applicant hypothesizes that the requisite insulin resistance of PCOS must be expressed initially during pubertal progression. Cross- sectional and longitudinal studies will describe the patterns of insulin sensitivity that emerge throughout puberty in young women. Initially, the applicant will contrast the insulin sensitivity achieved on frequently sampled intravenous (iv) glucose tolerance tests between two matched sets of 25 subjects from families with, and without, histories of PCOS, at each of two distinct stages of puberty. He will then test the hypothesis that insulin resistance evolving throughout puberty in 40 girls at high risk for development of PCOS differs qualitatively and quantitatively in

48

Insulin

its pattern of expression, when compared with an equal number of adolescent controls. The applicant will measure specific biophysical and biochemical parameters to determine whether changes in these easily-obtained indices correlate with and predict changes in insulin sensitivity. To begin to elucidate the cellular mechanism for this unique form of insulin resistance, the applicant further proposes to obtain needle biopsies of insulin-responsive muscle from select subjects who demonstrate extremes of insulin sensitivity in the cross- sectional study. The applicant will assess the integrity and function of specific molecules necessary for cellular transmission of the insulin signal, to determine whether changes in these effectors might be responsible for evolving insulin resistance in at-risk individuals. This work will provide insight into the earliest relationship between PCOS and insulin resistance, at the whole-body and cellular level. Enhanced understanding of these fundamental events may permit earlier detection and intervention, thus preventing the profound physiological consequences of unabated T2DM associated with PCOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE IN TISSUE SPECIFIC IKKB TRANSGENICS Principal Investigator & Institution: Lee, Jongsoon; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Our studies in insulin resistant cells and animals, and type 2 diabetic patients showed that the IkappaB kinase, IKKbeta, plays a central role in acquired insulin resistance. In 3T3-L1 adipocytes and Fao hepatoma cells, activation of IKKbeta by treatment of TNF or by transfection of upstream kinase, NIK, or constitutively active IKK, induced cellular insulin resistance-decreased insulinstimulated Tyr phosphorylation of IR and IRSs. Inhibition of IKKbeta by specific inhibitors- high doses of salicylates (NaS) or aspirin (ASA)- or by transfection of dominant negative IKKbeta reversed TNF-induced insulin resistance. Treatment of high doses of NaS or ASA to type 2 diabetes patients or obese and insulin resistant animals reversed insulin resistance as judged by glucose tolerance test (GTT), insulin tolerance test (ITT) and hyperinsulinemic, euglycemic clamp studies. Hyperglycemia, hyperinsulinemia, and dyslipidemia are normalized by ASA treatment. Insulin signaling studies conducted with tissues isolated from the rodents show that insulinstimulated Tyr phosphorylation of IR and IRS are increased due to decrease in inhibitory Ser/Thr phosphorylation of IRSs. Heterozygous deletion (IkkBeta +/-) in mice reduced fasting glucose and insulin concentrations, and protected against the development of insulin resistance during high-fat feeding and in obese Lep-ob/ob mice. We also found that obese animals have higher IKK kinase activity than control animals. To study which tissue(s) are important for IKK-mediated insulin resistance and for the reversal of insulin resistance by salicylates, we generated mice expressing constitutively active IKKbeta in fat, muscle and liver with the hypothesis that increasing IKKbeta activity in animal tissues may itself induce insulin resistance. We now have colonies of all three tissue transgenic mice and found that fat- and liver-specific transgenic mice have developed insulin resistance as early as 4 week-old. We will characterize these mice to determine which tissue is responsible for IKKbeta-induced insulin resistance and how activation of IKKbeta in one tissue can induce whole body insulin resistance. These experiments will validate IKKbeta as a major mediator of insulin resistance and as a useful target for the discovery of new drugs to treat type 2 diabetes and insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

49

Project Title: INSULIN SIGNALING PATHWAYS REGULATING PKC BETA SPLICING Principal Investigator & Institution: Cooper, Denise R.; Professor; Biochem and Molecular Biology; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: provided by applicant): Insulin responsiveness in muscle, fat, and liver occurs via a complex network of signaling pathways that regulate metabolic processes including protein synthesis, glycogen synthesis, and glucose uptake. We reported that insulin rapidly regulated splicing of the pre-mRNA for PKCbetaII by enhanced exon inclusion. PKCBetaII and its alternatively spliced product, PKCBetaI, are involved in insulin signaling and have distinct functions in signaling pathways. Insulin regulation of alternative splicing occurs via activation of phosphatidylinositol 3-kinase (PI3-kinase) and possibly Akt and cPKC. Both kinases fulfill numerous roles in insulin signaling including nuclear actions. The splicing of PKCBetaII mRNA requires serine/arginine rich (SR) proteins that interact with the pre-mRNA to activate splice site selection for exon inclusion. We found that SRp40, one SR protein, is phosphorylated following insulin treatment in a P13-kinase dependent manner. Several kinases activated by P13kinase and its products could phosphorylate SR proteins. The regulation of SR protein phosphorylation in relation to exon inclusion is a novel observation since phosphorylation of SR proteins by growth factor signaling pathways constitutes a new form of regulating splicing in addition to tissue specific- and developmental/cell cycle dependent- regulation. We hypothesize that Akt, PKC, and perhaps other kinases activated by PI3-kinase may phosphorylate SR proteins in response to insulin in skeletal muscle, fat and liver to regulate splice site selection. We will examine 1) the cis-elements identified by scanner linking mutagenesis of an insulin-responsive heterologous minigene we have developed to study exon inclusion (i.e., 216 bp exon encoding the Cterminal 52 amino acids of PKCBII and flanking intron sequences) in vivo in cell culture, 2) if SR proteins are substrates for Akt2 and cPKC isozymes, 3) the mechanism of splice site selection by developing in vitro splicing assays where HeLa cell nuclear extracts are supplemented with nuclear extracts from insulin-treated cells to track splicing intermediates, and 4) whether PKCBII alternative splicing can be redirected using antisense oliogonucleotides to probe functional elements in vivo. Elucidation of the signaling pathways that regulate splicing will become more important as an increasing number of proteins derived from alternative splicing are shown to have opposing effects on metabolic processes. The mechanism by which insulin regulates a process utilized to confer diversity in many biological systems represents a fundamental signaling event. The regulation of alternative splicing of PKCBetaII mRNA provides a molecular link between insulin activation of PI3-kinase and the post-transcriptional regulation of gene expression. The receptor signaling pathways involved in alternative pre-mRNA splicing may provide for a greater diversity in proteomic complexity than previously recognized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INSULIN SIGNALING THROUGH GTP BINDING PROTEINS Principal Investigator & Institution: Pessin, Jeffrey E.; Professor; Physiology and Biophysics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-JUN-1996; Project End 31-MAY-2004 Summary: During our investigation of insulin-stimulated Ras-dependent signal transduction, we have identified an important GTP binding protein involved in the

50

Insulin

insulin signaling pathway leading to the translocation of GLUT4-containing vesicles to the plasma membrane. We have obtained substantially evidence demonstrating that not only can activation of the trimeric GTP binding protein Gq and/or G11 induce GLUT4 translocation but that this is a necessary event in the insulin-stimulation of GLUT4 vesicle translocation. In order to further investigate the functional regulatory role of Gq/G11 in insulin signal transduction, we plan to determine the upstream mechanism(s) responsible for the insulin-stimulated activation of Gq/G11 in adipocytes. In parallel, we will work downstream to identify the targets of Gq/G11 activation directly leading to the translocation of GLUT4- containing cargo vesicles and their relationship with the insulin-stimulated signal transduction pathway mediated by the activation of the PI 3-kinase. In order to accomplish these goals, we propose two overall specific aims using both biochemical and cell biological approaches to determine the functional role of Gq/G11 in the insulin-dependent signal transduction pathway leading to GLUT4 translocation. This will include the use of adipocyte differentiating mouse embryo fibroblasts derived from Gqalpha null, G11alpha null and double Gqalpha/G11alpha null mice and by determining the insulin- stimulated upstream activation mechanisms and downstream effectors of Gq/G11. We will also use subcellular fraction to determine if Gq/G11 and PI 3-kinase dependent pathways recruit distinct population of intracellular GLUT4-containing compartments, the sum of which then accounts for the full extent of insulin stimulation. This studies will be performed in parallel with time lapse confocal fluorescent microscopy to examine the real time trafficking of GLUT4-containing vesicles to determine the specific steps in the translocation process regulated by Gq/G11 (trafficking, binding and fusion with the plasma membrane. Finally, we will then identify and characterize the downstream tyrosine phosphorylated targets of Gq/G11 activation, with particular emphasis on the approximately 65 kDa insulin-stimulated tyrosine phosphorylated protein that coimmunoprecipitates with Gq/Gli. Together, these studies will provide novel information with regard to the complex insulin signal transduction pathway and mechanisms directly involved in the regulation of GLUT4 vesicle exocytosis and fusion with the plasma membrane. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN Principal Investigator & Institution: Hayes, Frances J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAR-2005 Summary: (taken from the application) The overall goal of this proposal is to define the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Conducting studies in normal men, lean first degree relatives of type II diabetic patients, obese men with normal glucose tolerance, and men with type II diabetes will permit determination of whether the interaction between insulin resistance and testosterone is independent of body weight and glucose tolerance. Given the significant cardiovascular morbidity and mortality associated with obesity and type II diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important public health implications and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders. Specific Aims 1-3 of this proposal will address the impact of insulin resistance on the reproductive axis in the male and will specifically: i) define the dose response relationship between increasing insulin resistance and testosterone secretion

Studies

51

in men; ii) localize the defect induced in the hypothalamic-pituitary-gonadal (HPG) axis by insulin resistance using frequent blood sampling studies as well as GnRH and hCG testing after endogenous gonadotropin blockade with a GnRH antagonist; and iii) examine the impact on the HPG axis of reducing insulin resistance with a thiazolidinedione in men with type II diabetes. Specific Aims 4 and 5 will address the impact of testosterone on insulin resistance and will specifically: iv) define the doseresponse relationship between increasing testosterone and insulin resistance by measuring insulin sensitivity with a glucose clamp after induction of hypogonadism with a GnRH agonist and again after both physiologic and pharmacologic testosterone replacement; and v) examine the impact of testosterone treatment on insulin resistance and glycemic control in type II diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causative determinants unequivocally defined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRACELLULAR REGULATORS OF INSULIN SIGNALING Principal Investigator & Institution: Lewis, Robert E.; Associate Professor; None; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-MAR-2006 Summary: The long term goal of this research is to define molecular mechanisms involved in the regulation of cell growth and development by insulin. The signal transduction pathways involved in these processes are not fully understood, through important integral components of several insulin-stimulated pathways have been identified and characterized. The central hypothesis of this proposal is that multiple, distinct signals manage from the insulin receptor (IR) cytoplasmic domain upon activation of the receptor tyrosine kinase, and that those signals act separately and/or in combination to elicit the pleiotropic effects on cell fate and metabolism that are characteristic of insulin action. This hypothesis will be tested by analysis of putative effectors of insulin action and manipulation of a chimeric receptor encoding the extracellular ligand binding domain of the colony-stimulation factor-1 receptor (CSF1R) and the cytoplasmic domain of the insulin receptor. Expression of the CSF1R/1R allows CSF-1 to mimic the ability of insulin and IGF I to initiate adipoblast differentiation and activate glucose transport without activation of endogenous insulin receptors Mutations within the cytoplasmic domain of the CSF1R/IR have been useful in examining potential intracellular mediators of insulin action. This model system will be used to examine the molecular mechanisms used by insulin and IGFI to regulate cell growth and development with emphasis on the following: The contribution of IR effectors and pathways to the mitogenic and differentiation-inducing effects of insulin. The potential of IR effectors to manipulate adipocyte gene expression and function. The mechanisms used by IR effectors to transmit insulin-induced survival signals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SYNDROMEN

INTRAMYOCELLULAR

LIPIDS

IN

HIV-LIPODYSTROPHY

Principal Investigator & Institution: Torriani, Martin; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2008

52

Insulin

Summary: (provided by applicant): The HIV lipodystrophy syndrome is a recognized complication of highly active antiretroviral therapy (HAART) that is characterized by fat redistribution and insulin resistance. Studies using 1H-magnetic resonance spectroscopy (1H-MRS) have shown strong correlation of insulin resistance with concentrations of intramyocellular lipids (IMCL) in patients with type 2 diabetes, obesity, and HIV-lipodystrophy syndrome. However, very few studies have investigated IMCL overaccumulation as a potential mechanism of insulin resistance in HIV-positive patients, and the ability of IMCL to predict insulin resistance compared to detailed measures of insulin dynamics and body-composition. Furthermore, the effect of HAART and lipolytic blockade on muscle lipid metabolism remains unknown. Investigation of mechanisms and surrogate markers of insulin resistance is critical in patients with HIV infection to guide preventive strategies for long-term increased cardiovascular risk. My first hypothesis is that IMCL are increased among insulin resistant, HIV-infected patients with the lipodystrophy syndrome, and IMCL correlates strongly with sensitive indices of fat redistribution and insulin resistance. We will quantify IMCL using 1H-MRS in HIV-infected patients with and without lipodystrophy and healthy controls, and examine relationships with detailed measures of body composition, insulin dynamics and glucose homeostasis. My second hypothesis is that lipid accumulation occurs prior to development of overt insulin resistance and is a critical pathophysiological component of the development of insulin resistance in HIVinfected patients. IMCL levels will be determined with 1H-MRS before and after initiation of HAART in acute and chronic therapy-na'fve HIV-infected patients. My third hypothesis is that chronic lipolytic blockade with Acipimox will decrease fat accumulation in muscle and improve insulin resistance in HIV-infected patients with lipodystrophy syndrome. We will measure IMCL levels during chronic therapy with Acipimox and examine relationships with dyslipidemia, insulin resistance and lipolysis rate. In summary, this proposal will utilize 1H-MRS as a novel technique to investigate metabolic changes of muscle in the HIV-lipodystrophy syndrome and determine the role of IMCL in the pathogenesis of insulin resistance in this population, in addition, the natural history of IMCL will be followed in HIV-infected patients before and after the introduction of HAART and during chronic lipolytic blockade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEPTIN INDUCED REVERSAL ON INSULIN RESISTANCE IN OBESITY Principal Investigator & Institution: O'doherty, Robert M.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 15-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the applicant's abstract) Skeletal muscle resistance is a major contributor to the hyperglycemia, hyperinsulinemia and dyslipidemia associated with type II diabetes and obesity. Recent work has implicated leptin, the adipocyte-derived hormone, in improving insulin sensitivity. Thus, leptin administration to leptindeficient ob/ob mice corrects hyperglycemia and hyperinsulinemia, while elevating leptin in normal rats increases insulin sensitivity. Based on these observations the effects of leptin on the metabolic abnormalities of the high-fat fed rat, a model of dietinduced obesity that more closely resembles human obesity than monogenetic obesity models, were investigated. These studies, performed by the P.I. and discussed in this proposal, demonstrate that a gene therapy intervention that elevates plasma leptin levels reverses the skeletal muscle insulin resistance and other metabolic abnormalities associated with diet-induced obesity. However, the mechanisms underlying these

Studies

53

effects are unknown. This proposal, therefore, focuses on identification of the mechanisms underlying leptin-induced reversal of skeletal muscle insulin resistance in diet-induced obesity. Three specific aims will test the hypotheses that skeletal muscle insulin resistance by leptin. These variables have been implicated in the pathogenesis of insulin resistance and the determination of muscle insulin sensitivity, and are altered by leptin. Identification of the mechanisms mediating leptin-induced reversal of muscle insulin resistance may serve as a platform for the rational design of pharmaceutical or genetic therapy of insulin resistance in human obesity and type II diabetes. Specific Aims: 1. To determine the role of altered lipid metabolism in mediating leptin-induced improvements in insulin sensitivity. 2. To determine the role of altered activity of the insulin signaling pathway in mediating leptin-induced improvements in insulin sensitivity. 3. To determine the role of altered metabolic gene expression in mediating leptin-induced improvements in insulin sensitivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID REGULATED KINASES IN INSULIN ACTION Principal Investigator & Institution: Farese, Robert V.; Professor; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2001; Project Start 01-AUG-1987; Project End 31-DEC-2002 Summary: Mechanisms that underlie clinical insulin resistance will only be clarified when we more fully understand how insulin controls metabolic processes, in particular, glucose transport. During the past decade, it has become increasingly clear that bioactive lipids and lipid- regulated signalling factors play important roles in the mechanisms whereby insulin controls glucose transport and other metabolic processes in muscle and adipose tissues. From very recent findings, it also appears that: (a) small G-proteins, Rho and ARF, are involved in the activation of certain insulin-sensitive lipid-signalling pathways; (b) protein kinase C-zeta (PKC-zeta) is rapidly activated by insulin; and (c) both Rho and PKC-zeta may play an important role in glucose transport. The hypothesis that will be tested presently is that glucose transport is regulated, at least in part, by insulin-induced alterations in: (a) phosphatidylinositol (PI) 3-kinase and a functionally inter- related small G-protein, Rho; (b) bioactive lipids, most notably, D3PO4 derivatives of PI; and (c) downstream protein kinases, including PKC- zeta. We postulate that insulin, through PI 3-kinase, regulates Rho and PKC-zeta and both Rho and PKC-zeta, in turn, are required for, and may actively participate in GLUT4 translocation and glucose transport (see Fig. 1). We also postulate that GTPgammaS can enter this signalling pathway by activating Rho and PI3-kinase. The specific aims are to: 1. Define the role of PI 3-kinase during insulin-induced activation of Rho. 2. Determine whether Rho is upstream of PKC-zeta in the action of insulin or GTPgammaS. 3. Define the role of PI 3-kinase in insulin-induced activation of PKC-zeta. 4. Examine the roles of PKC-zeta and Rho in insulin-stimulated glucose transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MAPPING CONTACT POINTS OF INSULIN AND ITS RECEPTOR Principal Investigator & Institution: Katsoyannis, Panayotis G.; Pharmacology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Insulin is of central importance in human health and provides a general model for studies of protein structure and recognition. How does the hormone bind to the insulin receptor? How does its three-dimensional structure change in the hormone-

54

Insulin

receptor complex? Of both basic and applied importance, these questions will be investigated by synthetic, biochemical and structural approaches. The following Specific Aims are proposed: Aim 1-Toward the Receptor-Active Structure of Insulin: Multidimensional NMR Studies of Paradoxical Analogs. Crystal structures of insulin are now appreciated to represent inactive conformers of the hormone. To deduce the receptor-active structure, we will synthesize active analogs with predicted non-native structures. Of particular interest will be comparison of analogs containing corresponding D and L amino-acid substitutions. Solutions structures will be determined by NMR. Aim 2-Mapping the Insulin Receptor by Novel PhotoCrosslinking Analogs. Contact points between insulin and the receptor will be determined by synthesis of A- and B-chain analogs containing a photoactivatable crosslinking amino acid (L-para-azido-Phe). Sites of covalent attachment in the receptor will be mapped by protease digestion and direct micro sequencing. Aim 3-Mapping the Insulin-like Growth Factor I (IGF-I) Receptor. Determination of contact points between this growth factor and its receptor will be pursued by the procedures outlined in Aim 2 above, using as parent compound an IGF-I analog consisting of a two-chain molecule embodying the A domain of IGF-I and the B domain of insulin or IGF-I. The feasibility of our Aims are in each case demonstrated by preliminary results. This competing application thus offers the exciting possibility of integrating nonstandard peptide chemistry with biochemistry and biophysics to investigate fundamental aspects of insulin action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS AND EFFECT OF DECREASED GLUCOSE INSULIN SENSITIVITY IN PREGNANT WOMEN Principal Investigator & Institution: Catalano, Patrick M.; Professor; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: The long term objectives of this grant proposal are to investigate the mechanisms and effect of pregnancy on glucose insulin sensitivity in women with normal glucose tolerance (NGT) and gestational diabetes (GDM). The specific aims of this proposal are to: 1) determine the relationship between the changes in glucose insulin sensitivity and level of expression of post receptor insulin signaling intermediates in skeletal muscle in lean and obese women with NGT and GDM in late gestation and postpartum, 2) to determine the role of tumor necrosis factor alpha (TNFalpha) modulation of insulin receptor beta (IRbeta) and insulin receptor substrate I (IRS-1) in skeletal muscle in late pregnancy and 3) to characterize the effect of pregnancy on glucose metabolism, i.e. insulin sensitivity and pancreatic beta cell response postpartum in women with NGT and GDM. Specific aim #1 will evaluate longitudinally 12 women with NGT (6 lean and 6 obese) matched with 12 women with GDM (6 lean and 6 obese) at 30-36 weeks and 16 weeks postpartum. All subjects will be evaluated using the euglycemic clamp with infusion of [66/2/H2] glucose and have Bergstrom needle skeletal muscle biopsies. The specific methodology will allow us to estimate insulin sensitivity using Western blotting to measure changes in protein expression and competitive PCR to compare differences in mRNA expression during and after pregnancy. Specific aim #2 will evaluate 16 women at the time of elective cesarean delivery (8 NGT) and gynecologic surgery (8 CTL). All subjects will have densitometry and rectus muscle biopsies at the time of surgery. Skeletal muscle will be used to immunoprecipitate IRbeta and IRS-1. IRS-1 from pregnant NGT will be incubated with IRbeta from non pregnant CTL and insulin added to phosphorylate

Studies

55

IRbeta. This will allow us to evaluate if the rise in TNF- alpha in late pregnancy induces serine phosphorylation of IRS-1 and converts IRS-1 to an inhibitor of IRbeta tyrosine kinase activity. Specific aim #3 will evaluate 24 women; 8 women (4 NGT and 4GDM) who do not plan to conceive (at yearly intervals), and 16 women (8 NGT and 8 GDM) planning to conceive (prior to conception, at 30-36 weeks and post partum. All subjects will be evaluated using densitometry, an intravenous glucose tolerance test, indirect calorimetry and the euglycemic clamp with infusion of [6-6/2H2] glucose. These data will allow us to evaluate the effect of pregnancy on pancreatic beta cell function and insulin sensitivity in women with NGT and GDM, in contrast to changes in thee measurements ascribed to time alone. The information obtained from these studies will allow us to begin to understand the mechanisms involved in the alterations in insulin sensitivity during pregnancy, and the potential genetic factors responsible for decreased glucose insulin sensitivity in women with GDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CVD AND ENDOTHELIAL DYSFUNCTION IN OBESITY Principal Investigator & Institution: Hsueh, Willa A.; Professor of Medicine and Chief; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Endothelial cell (EC) dysfunction occurs early in the process of insulin resistance and, indeed, may be an integral component of the dysmetabolic syndrome. We hypothesize that adipokines contribute to both insulin resistance and EC dysfunction, possibly by increasing sensitivity to Angiotensin ll (Angll), in part by altering the balance between the activity of the phosphoinositol-3kinase (Pt3K) and mitogen activated protein kinase (MAPK) pathways. As a result, the progression of insulin resistance to type 2 diabetes parallels the progression of EC dysfunction to atherosclerosis. Specific Aims will be to determine: 1) The relationship of circulating adipokines to EC function in insulin sensitive (IS) vs. insulin resistant (IR) Mexican Americans (MA). The IR MA will include the spectrum of insulin resistance: early IR, IGT, and type 2 diabetes. EC function will be measured by coronary PET scanning. 2) Whether IR subjects have increased sensitivity to AngII infusion vs. age and gender-matched IS subjects as measured by blood pressure, suppression of plasma renin activity, increasing circulating hsCRP and adipokine levels, and stimulation of plasma aldosterone 3) The effect of AnglI AT1 receptor blocker (ARB) administration on insulinmediated glucose uptake, EC function, and circulating adipokines and inflammatory markers in IR subjects. 4) The correlations of insulin sensitivity and EC function with measurements of inflammatory gene expression, MAPK and PI3K activity in subcutaneous fat biopsies of IS vs. IR subjects and of (IR) subjects before and after treatment with an ARB. 5) The correlation of EC function with insulin sensitivity, circulating adipokines, and fat adipokine expression in the Zucker lean vs. obese rat models. The results of these investigations will help to 1) identify potential mechanisms by which adipokines alter signaling mechanisms and increase sensitivity to Angll to impair EC function and 2) determine the effect of RAS inhibition on adipokine levels and expression as related to insulin-mediated glucose uptake and EC function. These studies potentially have direct clinical applications as they promise to determine where in the spectrum of insulin resistance and EC dysfunction RAS inhibition is warranted to prevent development of the endpoints of diabetes and atherosclerosis. Early

56

Insulin

intervention is critical if we are to prevent these two major diseases, which may, indeed, be the same disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEMBRANE INTERACTIONS

RECEPTORS

AND

RECEPTOR

/LIGAND

Principal Investigator & Institution: Shipley, Graham; Professor; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 30-SEP-1985; Project End 31-DEC-2005 Summary: We have described the structures of the full-length LDL, and insulin receptors in both their detergent and vesicle-reconstituted forms. The objectives now are to extend our structural studies of both receptors to higher resolution and to examine the interactions with their ligands, LDL and insulin. For the LDL receptor, we will use the purified bovine receptor, as well as the expressed human LDL receptor and constructs of its extracellular domain(s). Our research is directed to the following goals: (1) use gold-labeled LDL receptor (bovine and human) and LDL receptor extracellular domains (human) to localized the receptor-binding domains of the LDL receptor; (3) use the C-terminal cysteine to bind extracellular domains of the LDL receptor to lipid monolayer surfaces; (4) perform structural studies of oriented LDL receptor and 2-D arrays by electron microscopy; (4) use oriented extracellular domains to bind and oreint LDL for structural studies by electron microscopy (with Project 3); (5) using CD and calorimetry, to define the secondary structure, conformation and unfolding of the human LDL receptor and its expressed extracellular sub-domains. We will continue our structural studies of the insulin receptor and its extracellular domain with the following goals: (1) to engineer terminal cysteine sites at the C-terminal of the extracellular domain of the insulin receptor for gold labeling and binding to lipid monolayer surfaces; (2) to use supported lipid monolayers to orient the extracellular insulin-binding domain of the insulin receptor; (3) to produce oriented 2-D arrays of the extracellular domaisn of the insulin receptor; (4) to use electron microscopy to define the structure of insulin receptor extracellular domain oriented at lipid surfaces; and (5) to study the effect of insulin binding on insulin receptor extracellular domain structure. Improved structural descriptions of the LDL and insulin receptors, as well as their interaction with their ligands LDL and insulin, should result. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT

ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Barry-Carr, Darcy; Obstetrics and Gynecology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): Pre-eclampsia, a hypertensive disorder unique to pregnancy, is a leading cause of maternal and neonatal morbidity and mortality. Endothelial dysfunction is a central feature in the pathophysiology of pre-eclampsia. Mechanisms that have been suggested to contribute to the endothelial dysfunction of pre-eclampsia include insulin resistance and a hyperdynamic circulation (high cardiac output). Insulin resistance and high cardiac output persist postpartum, suggesting that these women have an underlying disorder. However, it is unclear whether these abnormalities are related and whether insulin resistance has a role in producing hemodynamic alterations and endothelial dysfunction

Studies

57

in these women. The investigator hypothesizes that postpartum women who have a history of pre- eclampsia are insulin resistant and have associated alterations in hemodynamics and endothelial function. Furthermore, she hypothesizes that insulin resistance has a causal role in producing these changes. Two specific aims have been identified to address these hypotheses: 1) to determine whether the insulin resistance present in postpartum women with a history of pre-eclampsia is associated with altered hemodynamics and endothelial dysfunction; and 2) to determine whether reversing insulin resistance in women with a history of pre-eclampsia, is associated with improvements in hemodynamics and endothelial function, thus suggesting that insulin resistance is a causative factor in women with these abnormalities. A case-control study will address the first specific aim. A double-blind, placebo-controlled, randomized study will address the second specific aim by using an insulin sensitizing agent, rosiglitazone, as an interventional tool. The results of these studies could provide a rationale for future investigations aimed at determining whether treating insulin resistance in women with a history of pre-eclampsia will decrease the risk of recurrent pre- eclampsia in subsequent pregnancies and reduce the prevalence of the long-term metabolic and cardiovascular complications in these women as they age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Mclaughlin, Tracey L.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): The goal of the proposed research is to define the roles played by resistance to insulin-mediated glucose disposal (insulin resistance) and circulating insulin concentrations as factors affecting: 1) the ability of obese individuals to lose weight; and 2) risk for CHD in both nondiabetic individuals and patients with Type 2 diabetes. These issues are important, as the prevalence of obesity in the U.S. has reached epidemic proportions, and is contributing to an increase in Type 2 diabetes and CHD. While obesity, insulin resistance, and diabetes are highly associated, it is not clear whether insulin resistance and compensatory hyperinsulinemia play important roles in the tendency to gain weight and/or inability to lose weight. The role of hyperinsulinemia in CHD is also unclear. In this regard, the specific aims of the proposed research are as follows: 1) to compare insulin resistant versus insulin sensitive nondiabetic, overweight individuals with respect to their ability to lose weight on a low calorie diet. CHD risk factors before and after weight loss will also be assessed to determine the degree to which insulin resistance is associated with increased CHD risk in non-diabetic overweight individuals, as well as the impact that differences in insulin resistance have on the metabolic benefits of weight loss. 2) To determine if weight loss and its associated metabolic benefits vary as a function of the relative amounts of dietary fat and carbohydrate in hypocaloric diets. Because high carbohydrate diets increase insulin secretion, the relationship between dietary composition and change in circulating insulin concentrations will be analyzed with respect to both weight loss and CHD risk factors. 3) To quantify and compare the improvement in glycemic control and CHD risk factors associated with weight loss in obese Type 2 diabetics, while being treated with: a) an insulin secretagogue (sulfonylurea); or b) an insulin sensitizer (thiazolidenedione). Manipulation of plasma insulin concentrations with these medications will provide a

58

Insulin

mechanism by which to evaluate the impact of circulating insulin concentrations on the described outcome measurements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS OF INSULIN PRODUCTION IN ENTEROENDOCRINE CELLS Principal Investigator & Institution: Zhukova, Elena; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Diabetes mellitus, a chronic group of disorders characterized by hyperglycemia, remains a major cause of premature disability and mortality in United States. Patients with type I diabetes have little or no insulin secretory capacity, and the primary focus for their treatment is to replace insulin secretion by the administration of exogenous insulin. However, optimal glycemic control is often difficult to achieve. The broad, long-term objective of this proposal is to engineer a system in which insulin secretion in response to food intake will ensure tight control of blood glucose levels. As a first step in devising gene therapy strategies for treatment of diabetes, we have chosen to utilize the gastrin-secreting G cells of the stomach to produce surrogate a cells. Our central hypothesis is that human insulin, produced by G cells under the regulation of the gastrin gene promoter, would be secreted hi response to meal-associated stimuli. In order to explore this hypothesis, we have demonstrated that the gastrin promoter can target expression of insulin to G cells and, consequently, we are generating transgenic knock-in mice G-InsKI, in which the coding sequence of human insulin is knocked into the mouse gastrin gene. Specifically, insulin produced by and stored in the gastric G cells of G-InsKI mice is envisaged to be released in response to either hormonal regulators, including bombesin/GRP, or by luminal regulators, including aromatic amino acids, Ca 2+ and tastants. These stimuli act directly via specific G protein-coupled receptors on the surface of G cells. The elucidation of the signaling pathways involved could provide novel therapeutic approaches to regulate the production and secretion of insulin from the G cells. Our central hypothesis will be tested by pursuing the following specific aims: 1: Characterize G-InsKI mice and assess regulated release of insulin from the gastric G cells in G-InsKI mice. 2: Identify the signal transduction pathways that control the secretion of insulin from gastrointestinal endocrine cells using the hormone secreting enteroendocrine STC1 cell line as a model of G cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MODULATION OF PANCREATIC ENDOCRINE FUNCTION Principal Investigator & Institution: Tobin, Brian W.; Plant and Soil Science; Mercer University in Atlanta 3001 Mercer University Dr Atlanta, Ga 30341 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: (Scanned from the applicant's abstract) Ground based and in-flight investigations illustrate changes in insulin, glucose, and amino acid metabolism during spaceflight. These observations may relate to altered pancreatic endocrine function which is insufficient to meet the needs of microgravity induced insulin resistance, and altered amino acid metabolism. The changes observed include decreased glucose tolerance, increased circulating insulin, and increased reliance upon glucose in muscles. The metabolic milieu resembles an insulin resistant syndrome, accompanied by a compensatory increase in pancreatic insulin secretion. However, the increase in insulin

Studies

59

secretion is insufficient to ameliorate muscle atrophy. The increased insulin secretion is well correlated to muscle atrophy in spaceflight. There is not much known about the effects of microgravity on the other islet hormones glucagon and somatostatin. Both are key players in islet and metabolic physiology. Countermeasures which could modulate insulin, glucagon and somatostatin secretion in a compensatory manner to overcome insulin resistance and promote amino acid uptake by peripheral musculature might decrease muscle atrophy and reduce injury following re-adaptation to unit gravity. We hypothesize that human pancreatic islets of Langerhans have an increased requirement for amino acids in microgravity. We further hypothesize, that supplementation with specific additional amino acids will augment, enhance and normalize insulin secretion, when spaceflight paradigm stressors known to decrease insulin secretion, are applied. Our specific aims in this study are to: 1) assess the effect of a microgravity model cell culture system on basal endocrine secretory function and amino acid requirements in human islets of Langerhans, and 2) determine human islet endocrine function while testing amino acid countermeasures in the microgravity model. It is anticipated that these studies will further refine our understanding of human pancreatic amino acid requirements and endocrine regulation; phenomenon which may be limiting to extended-duration spaceflight missions. These studies will test countermeasures to augment pancreatic endocrine function, while considering both insulin and glucagon production in a way that will involve supplementation of diet with additional amino acids. These measures are ultimately aimed at improving spaceflight induced muscle atrophy, and ameliorating current re-adaptatinn constraints. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DEFECTS OF INSULIN SIGNALING IN PCOS Principal Investigator & Institution: Azziz, Ricardo; Professor and Chairman; CedarsSinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The polycystic ovary syndrome (PCOS) affects about 4% of reproductive-aged women, and is one of the most common causes of oligoovulatory infertility. Between 50% and 70% of women with PCOS demonstrate insulin resistance, independent of body weight, and the resulting compensatory hyperinsulinemia leads to the hyperandrogenic features of the disorder. Overall, little is know about the molecular aspects of the insulin signaling defects of PCOS. Previous studies have indicated that insulin-stimulated glucose transport is deficient, suggesting an alteration along the PI-3 kinase/Akt/GLUT-4 cascade. Alternatively, mitogenic activity in response to insulin appears to be normal in the fibroblasts of these patients, suggesting that the MAPK pathway may be unaffected in PCOS. Based on these observations we have hypothesized that abnormal insulin receptor (IR) signaling in adipose tissues is a frequent abnormality in women with PCOS; and that the defect is present downstream from the IR, affecting the PI-3 kinase/Akt/GLUT-4, but not the MAPK, pathway. We have also hypothesized that the insulin resistance of PCOS may be more closely related to abnormalities of visceral (omental) than subcutaneous fat. Our Specific Aim is to determine whether abnormal IR signaling is present in the adipocytes of patients with PCOS. Specifically, we will test our hypothesis by studying the abdominal subcutaneous and omental adipose tissues of 10 normal-weight or pre-obese PCOS patients and 10 age/race/body massmatched controls. In these tissues we will determine: i) the total amount and the degree of phosphorylation in response to insulin of the IR, the IR substrate-1 and 2 proteins (IRS-1/2), and of critical intermediate proteins (i.e., Akt, GSK-3, and FKHR of the PI-3 kinase/Akt cascade; c-Raf, MEK-1,

60

Insulin

ERKI/2, and p90RSK of the ERKI/2 cascade; JNK of the SAPK/JNK cascade; and p38 MAPK of the cascade of the same name) and the translational regulator p70 S6; and ii) the total amounts of GLUT-4 and IRS-associated PI-3 kinase. We should note that this systematic approach to investigating insulin signaling is critical at this early stage in the study of the mechanisms underlying insulin resistance in PCOS. Long term, these studies have the potential of eventually elucidating the etiologic mechanism(s) in some, or most, patients; helping to develop targeted therapies; and guiding the search for molecular markers for PCOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PHARMACOLOGY OF INSULIN RESISTANCE IN BURNS Principal Investigator & Institution: Martyn, J Jeevendra.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-MAR-2006 Summary: (provided by applicant) The hypermetabolic state of burns is associated with uncontrolled catabolism of proteins, fat and carbohydrates, and affects morbidity and mortality. The associated major metabolic anomaly is resistance to the effects of insulin, the pivotal anabolic hormone. Among the signaling cascades activated by insulin, the insulin receptor (IR), insulin receptor substrates (IRSs), phosphatidylinositol-3phosphate kinase (PI 3-K) and Akt/PKB are central for energy metabolism and glucose homeostasis. Activated Akt/PKB in turn inhibits its downstream molecule, glucose synthase kinase-3 (GSK-3), resulting in increased protein and glycogen synthesis. Altered activation of all these signaling molecules occurs following burn injury, but the molecular mechanisms inducing these changes have not been elucidated. Many cytokines are expressed locally and systematically following burn injury, leading to increased expression of inducible nitric oxide (iNOS), and release of high levels of nitric oxide (NO). Based on compelling and convincing preliminary data, we hypothesize that iNOS, via release of NO with superoxide, plays an important role in insulin resistance of burn by altered signaling via IR, IRSs, PI 3-K, Akt/PKB and GSK-3. The following Specific Aims will test the above hypothesis in burn/sham-injured rodents in vivo, in cultured cells and in reconstituted in vitro systems: Specific Aim 1 will test the hypothesis that iNOS is required for insulin resistance. Specific Aim 2 will test the hypothesis that the exaggerated production of NO by iNOS decreases tyrosine kinase activity of IR and tyrosyl phosphorylation of IRSs. The molecular mechanism of inactivation of JR and IRSs (S-nitrosylation vs. nitration) will also be identified. Specific Aim 3 will test the hypothesis that the exaggerated production of NO by iNOS alters the kinase activity of Akt/PKB, the further downstream molecule of PI 3-K, independent of IR and IRSs. The molecular mechanisms responsible for inactivation (post-translational modifications) of Ak/IPKB by NO will also be identified. Specific Aim 4 will test the hypothesis that exaggerated production of NO by iNOS increases activity of GSK-3, due to effects related to both decreased AktJPKB activity and direct effects of NO on GSK-3. The direct role of NO on activation of GSK-3 (independent of AktIPKB) will be tested with NO donors and scavengers. The in vivo studies will include the use of burn and sham-injured rats, and iNOS knock out (-/-) and wild type (+/+) mice. Insulin mediated signaling changes, and the post-translational modifications in the signaling molecules enumerated above with and without specific iNOS inhibitor (1400W) will be evaluated. Functional changes, evaluated using 2-deoxyglucose uptake in muscle and adipocyte, will be correlated to signaling changes. Using adipocyte and myocyte cell lines and primary cultures from iNOS -/- and iNOS +/+ mice, the role of iNOS/NO will

Studies

61

be evaluated with and without NO donors or scavengers. The role of NO will be confirmed in in vitro reconstitution system containing active signaling molecules. The post-translational modifications (nitration vs. S-nitrosylation) associated with 1NOS/NO will be studied by biochemical, spectrophotometric and immunoblot techniques. Several lines of evidence suggest that protein S-nitrosylationldenitrosylation and tyrosine nitration/denitration may serve as regulatory components. The involvement of NO in insulin resistance will be assessed in the light of this new concept. The immediate short-term goals of these studies are, therefore, to characterize the molecular and biochemical mechanisms inducing insulin resistance, so that in the long-term, insulin resistance of burn injury in humans can be reversed. The studies together will thus provide significant insights into the pathogenesis of insulin resistance and provide information on novel therapeutic strategies to treat burn, and other stress or inflammation-induced insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR REGULATION OF MUSCLE GLUCOSE METABOLISM Principal Investigator & Institution: Mandarino, Lawrence J.; Professor; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAY-2002 Summary: Insulin resistance in skeletal muscle contributes to the metabolic derangements in obesity and Type II (non-insulin dependent) diabetes mellitus (NIDDM). Although major advances have been made in understand the mechanisms by which insulin signals its effects in muscle, much less is known regarding how abnormalities in insulin signaling contribute to insulin resistance in this tissue. We have shown that although insulin stimulated insulin receptor tyrosine phosphorylation is considerably reduced in muscle biopsies from patients with NIDDM, with consequent decreased in IRS-1 and PI 3-kinases signaling, insulin normally activates the MAP kinases cascade in these very insulin resistant patients. The overall goal of this proposal is to further characterize insulin resistance with respect to the PI 3-kinase pathway in obese and NIDDM patients and to begin to discern the mechanisms responsible for the discordance in insulin resistance with respect to the PI 3-kinase pathway in obese and NIDDM patients and to begin to discern the mechanisms responsible for the discordance insulin signaling to the PI 3-kinase and MAP kinase pathways. Specifically, we propose 1) To determine the nature of the abnormalities in insulin signaling in muscle from patients with Type II diabetes. We will test the hypothesis a) that the maximal response is reduced and the time course is altered, and we will continue to explore the mechanisms underlying our observation that insulin resistance is restricted to PI 3-kinase and does not affect the MAP kinase pathway, 2) that IRS-2 signaling is regulated differently than IRS-1 in muscle of diabetics, and 3) that the IGF-I receptor or IGF-1/insulin hybrid receptor are activated by insulin, and could potentially contribute to signaling to the MAP kinase pathway. We also propose 2) to more closely examine the mechanisms involved in the decrease in insulin stimulation or insulin receptor tyrosine phosphorylation in muscle from Type II diabetics. We will test the hypothesis that a) insulin receptor tyrosine kinase (IRTK) activity is not as reduced as insulin receptor autophosphorylation, especially toward exogenous substrates, b) increased serine phosphorylation of the receptor inhibits tyrosine phosphorylation in diabetics, and 3) that the inhibitory protein Grb-IR association with the insulin receptor is greater in diabetics than in control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

62

Insulin

•

Project Title: MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE Principal Investigator & Institution: Dohm, Gerald L.; Professor; Biochemistry; East Carolina University 1000 E 5Th St Greenville, Nc 27858 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2004 Summary: The long range objective of this research is to understand the molecular mechanism of insulin resistance in muscle tissue of obese individuals and diabetic patients. The most likely cause of insulin resistance in human muscle is decreased insulin receptor tyrosine kinase activity. The hypothesis is that hyperinsulinemia causes activation of PKC-beta which then serine/threonine phosphorylates and inactivates the insulin receptor to cause insulin resistance in muscles of obese individuals. It was previously demonstrated that: (1) insulin resistance can be induced by incubating insulin sensitive muscle with an activator of PKC. (2) Insulin action and insulin receptor kinase activity are restored in insulin resistant muscles that are treated with a PKC inhibitor. (3) PKC-beta is increased in muscle of obese individuals. (4) Insulin causes membrane associated PKC-beta to be increased in insulin resistant muscles. (5) Overexpression of PKC-beta decreases insulin signaling, and knockout of PKC-beta increases insulin signal transduction, in heart of transgenic mice. This proposal will continue to focus on the insulin receptor and PKC-beta to gain evidence to support the hypothesis. Specific Aim 1: To determine the phosphorylation pattern on the insulin receptor. Specific Aim 2: To investigate the role of hyperinsulinemia in activation of PKC-beta and phosphorylation of insulin receptors. Specific Aim 3: To study insulin action in muscle of PKC-beta knockout mice. Specific Aim 4: To study the serine/threonine phosphatase(s) that reactivates the insulin receptor. It will be possible to study these mechanisms because a large number of obese patients are available for study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEUTRAL LIPID DYSREGULATION OF THE PANCREATIC BETACELL Principal Investigator & Institution: Poitout, Vincent; Associate Professor; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Scanned from the applicant's description) Type 2 diabetes mellitus is characterized by chronic hyperglycemia and is often associated with elevated plasma lipid levels. The overall objective of this proposal is to ascertain the mechanisms whereby prolonged exposure to elevated levels of fatty acids (FA) affects pancreatic beta-cell function in Type 2 diabetes. Previously, we have demonstrated that prolonged exposure to FA impairs insulin gene expression only in the presence of high glucose, and that this is associated with increased neutral lipid synthesis. Specific Aim I: To identify the metabolic intermediate(s) generated along the pathway of neutral lipid synthesis responsible for the impairment of insulin secretion and gene expression upon prolonged exposure to FA. Isolated rat islets, HIT-T15, and betaHC-l3 cells will be cultured for 1 to 7 days in the presence of increasing concentrations of glucose and FA. Pharmacological tools will be used to inhibit or stimulate each step of neutral lipid synthesis, in order to identify the metabolic intermediate(s) generated along the esterification pathway (i.e., long-chain Acyl-CoA, diacyiglycerols, or triacylglycerols) responsible for the FA-induced impairment of beta-cell function. Specific Aim II: To assess whether the glucose-dependent deleterious effects of prolonged exposure to elevated FA on beta-cell function are glucose-specific, and whether the mechanisms of

Studies

63

these effects are transcriptional, post-transcriptional, or translational. beta-cell exhaustion will be distinguished from bona fide toxicity in experiments where diazoxide will be used to inhibit insulin release. The glucose-specificity of PA effects will be investigated by using a non-glucose secretagogue to stimulate insulin secretion and insulin gene expression. The glucose-dependent effects of FA on proinsulin biosynthesis, insulin mRNA stability, and endogenous insulin gene transcription will be assessed. The effects of FA on insulin promoter activity will be characterized in HITTl5 and betaHC-13 cells and also investigated in primary islets using the recombinant adenovirus system. Specific Aim III: To determine whether high-fat feeding in hyperglycemic Goto-Kakizaki (GK) rats impairs insulin secretion, insulin biosynthesis, and insulin gene expression, and whether these effects are prevented by normalization of blood glucose levels. GK or control rats will be fed a high-fat diet for 6 weeks, after which insulin secretion, proinsulin biosynthesis, and insulin gene expression will be assessed. Blood glucose levels will be normalized in GK rats by phloridzin administration, in an attempt to prevent the deleterious effects of high-fat diet on betacell function. These experiments will provide important insights into the pathophysiology of beta-cell dysfunction of type 2 diabetes, and have clear implications for the treatment of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHOSPHOPEPTIDE METABOLISM IN ADIPOCYTES Principal Investigator & Institution: Avruch, Joseph; Chief, Diabetes Unit and Professor of Me; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-JUN-1977; Project End 31-DEC-2003 Summary: The goal of this project is to describe in molecular detail one limb of the insulin signal transduction system. Nearly all of the classical metabolic responses to insulin require activation of the phosphatidylinositol 3' OH kinase (PI-3 Kinase). Thus to understand insulin signalling, the identity of the effectors of the PI-3 Kinase relevant to insulin must be identified and characterized. This project focuses on an outflow from PI-3 kinase to the protein (Ser/Thr) kinase known as p70 S6 kinase. This enzyme appears to be critical to the insulin control of protein synthesis, in particular to the process of ribosomal biogenesis, a crucial component of the anabolic response to insulin. We showed previously that p70 is regulated by insulin through a complex multisite phosphorylation directed at several different domains involving Thr252, Ser394, Thr412 and others, and catalyzed by an array of PI-3 Kinase-regulated protein kinases situated upstream. The activity of the p7O S6 kinase is also regulated by the availability of amino acids through a novel signal transduction pathway, largely distinct from that controlled by insulin, but which converges with the pathway controlled by the mTOR kinase, the target of the immuno- suppressant drug, rapamycin. This novel amino and mTOR responsive pathway may utilize protein phosphatases to control cell function. We recently discovered one of the enzymes responsible for the insulin activation of p70 S6 kinase. This enzyme, called PDK1 is also one of the activators of the cAkt/PKB kinase. PDK1 must work in conjunction with other, as yet unidentified Ptd Ins (3,4,5)P3 activated kinases, in order to activate effectively both p70 and PKB. The goals of this project for the next period are to: 1) Isolate and characterize the other PI-3 kinase-regulated protein kinase necessary for activation of p70, the p70 Thr412 kinase; 2 ) Characterize the protein kinase active on p70 Ser394 in vivo, and the nature and significance of mTO- catalyzed phosphorylation of p70; 3) Characterize the protein phosphatases that act on p70 and their regulation by insulin, amino acids an mTOR; 4) Characterize the regulation, cellular itinerary and cellular targets of PDK1, an important

64

Insulin

multifunctional PI-3 kinase effector. These studies will clarify several of the major new signalling outflows of the insulin receptor, and will provide new insights into the regulation of protein synthesis. These results will have implications for the design of new pharmacologic interventions in diabetes mellitus and will have wide implications for the nutritional regulation of body protein turnover. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSICAL ACTIVITY ON INSULIN RESISTANCE IN THE ELDERLY Principal Investigator & Institution: Evans, William J.; Professor; Geriatrics; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) Advancing age is associated with insulin resistance, glucose intolerance, and Type 2 diabetes. Regular higher-intensity aerobic exercise reduces insulin resistance and lowers the risk of Type 2 diabetes. Nonetheless, recent cross-sectional data, based on ACSM/CDC physical activity recommendations for moderate-intensity activity on most if not all days of the week (i.e., 1000 kcal/wk), demonstrate that insulin levels are lower with regular moderate-intensity activity in middle-aged adults, suggesting a reduction in insulin resistance. Despite these crosssectional data, few well-controlled prospective studies have determined if these recommendations are appropriate to reduce insulin resistance in the elderly. Because higher-intensity aerobic exercise is not practical for a large percentage of the elderly, data are needed to determine the efficacy of moderate-intensity exercise on reducing insulin resistance. Therefore, the primary aim of this study will be to examine the influence of 1000 kcal/wk of moderate versus higher-intensity aerobic exercise on insulin-simulated glucose disposal. A secondary aim will examine if moderate and higher-intensity aerobic exercise differentially influence non-exercising activity. Recent data in the elderly suggest that regular higher-intensity activities may reduce nonexercising activity during rest of the day. We will recruit 57, 65-90 y old women and men, who will be randomized into one of the following three groups: 1) Moderateintensity activity (1000 kcal/wk at 50 percent VO2peak; 2) Higher-intensity activity (1000 kcal/wk at 75 percent VO2peak); 3) Control. Subjects will complete 12 wk of aerobic cycling with pre and post-testing for insulin-stimulated glucose disposal via the hyperinsulinemic/euglycemic clamp, glucose tolerance by an OGTT, and body composition using dual energy x-ray absorptiometry. Physical activity levels will be assessed by structured questionnaire every 3 weeks. Our primary hypothesize is that 1000 kcal/wk of moderate or higher-intensity activity will be equally effective decreasing insulin resistance in the elderly. Our secondary hypothesis is that higherintensity activity will decrease non-exercising physical activity in the elderly. This New Investigator application will provide data to base future aerobic exercise recommendations in elderly adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PROPERTIES OF THE HIGH AFFINITY INSULIN RECEPTOR Principal Investigator & Institution: Czech, Michael P.; Professor; Biochem and Molecular Biology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 01-APR-1981; Project End 31-MAR-2004 Summary: The insulin receptor tyrosine kinase, through its action on RAS and PI 3kinase signaling elements, activates serine/threonine protein kinases and phosphatases

Studies

65

which in turn mediate its effects on metabolic and cellular processes. We developed a powerful new method to screen cDNA expression libraries for potential downstream effectors of the lipid products of PI 3-kinase. Using this method, we discovered the protein GRP1, which binds PtdIns(3,4,5)P3 through its PH domain and catalyzes guanine nucleotide exchange of ARF proteins through its Sec7 domain. This domain structure of GRP1 suggests a second paradigm for insulin receptor signaling based on the activation of ARF proteins. These GTP binding proteins appear to regulate such cellular processes as membrane budding and actin assembly, suggesting the model: IR yields IRS yields PI 3-kinase yields PtdIns(3,4,5)P3 yields GRP1 yields ARF yields bioeffect. The studies proposed here will test this novel hypothesis. Cellular sites of recruitment of GRP1 by insulin will be defined by immuno-microscopic methods to determine which cellular membrane systems might be targets of GRP1/ARF actions. We shall test whether insulin enhances ARF activation (GTP-binding), as does overexpression of GRP1. Whether GRP1 is required for this insulin action will be determined by gene knockout as well as expression of dominant inhibitory constructs of GRP1. We shall employ our cDNA expression library screening technique using 3' phosphoinositides as probes to test whether other GRP-like proteins are expressed in insulin sensitive cells that may act as downstream signaling elements. We shall also define the unique structural elements within the PH domain of GRP1 and related proteins that confer unique specificity for high affinity binding of PtdIns(3,4,5)P3. Finally, we shall determine whether GRP-like proteins and ARF proteins are required for biological effects of insulin (e.g., glucose transport, glycogen synthesis, lipolysis, membrane ruffling, cell adhesion). The experiments proposed may define a new paradigm for insulin signaling that involves the GTP-binding ARF proteins, and reveal novel elements in this signaling pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTOR 'TRANSACTIVATION' IN INSULIN SIGNALING. Principal Investigator & Institution: Luttrell, Louis M.; Associate Professor of Medicine; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Scanned from the applicant's abstract) In response to insulin, glucose transporters redistribute to the plasma membrane, glucose and lipid metabolism shifts into an anabolic mode, lipid kinases generate anti-apoptotic signals, and tyrosine kinases stimulate cell growth. Current models propose that insulin responses arise from the intrinsic ligand-stimulated tyrosine kinase activity of the receptor acting upon a small subset of tyrosine phosphoprotein adapters. Recent work, however, has begun to reveal extensive networks of cross talk between insulin family receptors and other signal transducers including heterotrimeric G proteins and classical receptor tyrosine kinases. In this proposal, we provide preliminary data demonstrating that IGF-1 receptors stimulate the anti-apoptotic IRS1/Phosphatidylinositol 3-kinase/Akt pathway and the proliferative Shc/Grb2-Sos/Ras/ERK1/2 pathway by distinct mechanisms. Whereas IGF- 1 receptor-mediated phosphorylation of IRS proteins controls the antiapoptotic pathway, IGF-1-induced mitogenic signaling requires the release of epidermal growth factor (EGF)like ligands from the cell surface and paracrine "transactivation" of EGF receptors. Cross talk between IGF- 1 and EGF receptors is mediated by matrix metalloprotease-dependent cleavage of heparin-binding (HB)-EGF, process which also involves pertussis toxin-sensitive heterotrimeric G proteins. The broad goals of this proposal are to characterize the mechanisms of cross talk between insulin/IGF-1 receptors, EGF receptors, and heterotrimeric G proteins, and to determine

66

Insulin

contribution of these mechanisms to transcriptional regulation and the control of cell proliferation by insulin and IGF- 1 receptors. One specific aim of this proposal to determine the mechanism whereby insulin and IGF- 1 receptors regulate matrix metalloproteases to control ectodomain shedding of EGF receptor ligands. Another aim is to determine the mechanism of cross talk between insulin/lGF- 1 receptors and heterotrimeric G proteins and to define the role of heterotrimeric G proteins in insulin and IGF- 1 receptor-mediated activation of the ERK1/2 MAP kinase cascade. The third aim is to determine the contribution of cross talk between insulin/lGF- 1 receptors, heterotrimeric G proteins and EGF receptors to transcriptional regulation and the control of cell proliferation in a variety of insulin-sensitive cell types. Experiments will employ immortalized cell lines, as well as cultured hepatocyte, adipocyte and muscle cells. Understanding these mechanisms may lead to pharmacologic approaches to dissociate the potentially harmful proliferative effects of insulin family receptors from their anti-apoptotic and metabolic effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF GLUCOSE-6-PHOSPHATASE GENE EXPRESSION Principal Investigator & Institution: O'brien, Richard M.; Associate Professor; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Type II, non-insulin dependent diabetes mellitus (NIDDM) is characterized by defects in insulin secretion, peripheral glucose utilization (PGU) and hepatic glucose production (HGP). The ability of insulin to stimulate PGU and repress HGP in patients with NIDDM is reduced as a consequence of insulin resistance. In addition, in Type I, insulin-dependent diabetes mellitus (IDDM), HGP can increase if circulating insulin levels are low or because poor glycemic control has led to the development of insulin resistance. Persistent hyperglycemia is the cause of many of the complications associated with diabetes. In both IDDM and NIDDM this increased HGP is a consequence of an increased rate of gluconeo-genesis. The final step of the gluconeogenic pathway is catalyzed by glucose-6-phosphatase (G6Pase). Recent data has shown that overexpression of the G6Pase catalytic subunit results in an increased rate of HGP. Thus, the suppression of G6Pase catalytic subunit gene expression may represent a potential strategy for reducing HGP in diabetic patients. The rational development of a pharmaceutical agent that suppresses G6Pase catalytic subunit gene expression will require a detailed knowledge of the cis-acting elements and trans-acting factors through which expression of the gene is regulated. Specific Aims 1 and 2 of this grant application propose to characterize the cis-acting elements and trans-acting factors that mediate the stimulatory effect of cAMP and the inhibitory effect of phorbol esters on G6Pase catalytic subunit gene transcription, respectively. This will be achieved using a fusion gene strategy in conjunction with the transfection of tissue culture cell lines as well as the generation of transgenic mice. From preliminary studies it is apparent that multiple cis-acting elements are required for the full effect of both agents. In addition, the cis-acting elements that mediate the stimulatory effect of cAMP in liver cells are distinct from those that mediate this effect in kidney cells. The inhibitory action of insulin on G6Pase catalytic subunit gene transcription requires two promoter regions designated A and B. Region A binds hepatocyte nuclear factor-1 (HNF-1) but does not directly mediate the action of insulin. Instead, HNF-1 enhances the action of insulin mediated through an unidentified transcription factor that binds Region B. The third

Studies

67

Specific Aim of this application proposes to explore several aspects of the mechanism of insulin action on G6Pase gene transcription. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HEPATIC INSULIN EXTRACTION Principal Investigator & Institution: Polonsky, Kenneth S.; Chief, Section of Endocrinology; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 31-DEC-2001 Summary: (Adapted from Applicant's Abstract): The overall goal of this project is to study the effects of specific diabetes susceptibility genes on insulin secretion and to define clinical protocols which describe the altered pattern of secretion associated with expression of these genes. Since susceptibility genes for the common form of late-onset NIDDM have not yet been identified, MODY will be used as an experimental model. Three genetic subtypes of this condition (MODY1, MODY2, and MODY 3) have been identified each being linked to a separate susceptibility locus. Studies will be performed in subjects with the three forms of MODY to further define the insulin secretory responses to glucose and non-glucose stimuli on physiological testing. A specific attempt will be made to determine whether defects in insulin secretion are present in subjects genetically predisposed to MODY prior to the onset of overt hyperglycemia. Complementary studies will be performed in a mouse model in which one allele of the glucokinase gene has been knocked out. Heterozygous animals have reduced expression of glucokinase in the B-cell and liver and in this respect resemble subjects with MODY2 in which the mutation in the enzyme glucokinase results in production of an inactive enzyme. Using the isolated perifused pancreas and isolated perfused islets we propose to study responses to non-glucose stimuli in these animals, alterations in oscillatory insulin secretion and the ability of animals lacking one glucokinase allele to compensate for mild hyperglycemia and insulin resistance. It is proposed to explore the mechanisms associated with altered insulin secretion in subjects with impaired glucose tolerance by determining if they are reversible by treatment with metformin, a biguanide which lowers glucose levels by suppressing hepatic glucose production and troglitazone, a novel agent which appears to reduce peripheral insulin resistance. We will also determine whether subjects with impaired glucose tolerance are able to increase insulin secretion in response to infusion of a triglyceride emulsion and heparin, a combination which increases insulin resistance by increasing the concentrations of free fatty acids. It is anticipated that these studies will provide mechanistic insights into the role of abnormal B-cell function in the pathophysiology of NIDDM. By allowing the manifestations of the insulin secretory defects present in subjects with impaired glucose tolerance to be compared with those present in MODY, these studies should define experimental approaches which will uncover B-cell dysfunction at an early stage in the development of NIDDM even before the onset of overt hyperglycemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: REGULATION OF INSULIN ACTION: ROLE OF NITRIC OXIDE Principal Investigator & Institution: Shankar, R R.; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Insulin resistance is thought to be one of the primary pathogenic mechanisms that is responsible for the phenotype and

68

Insulin

complications associated with type 2 diabetes mellitus (T2DM) and obesity. Insulin is uniquely capable of modifying it's action, because insulin, in addition to the direct effect of enhancing tissue glucose uptake, also modulates the delivery of substrate and insulin by affecting blood flow, especially to skeletal muscle. The vascular effects of insulin are mediated through the release of nitric oxide (NO) which is formed when the enzyme nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrulline. Both the direct tissue effect, as well as the vascular effect of insulin is blunted in subjects with insulin resistance. The exact mechanisms that induce insulin resistance are not yet clear. We have described insulin resistance in several animal models: 1) Systemic administration of L-NMMA (a competitive inhibitor of NOS) in rats results in hypertension and insulin resistance. 2) Administration of L-NMMA into the lateral cerebral ventricle of rats also results in hypertension and insulin resistance. 3) Mice with targeted disruption of the endothelial as well as neuronal NOS isoforms (eNOS and nNOS respectively) have been described to be hypertensive. We recently demonstrated insulin resistance in both these knockout mice, raising the possibility that NOS activity and NO production may play an important role in regulating insulin action and causing insulin resistance. However, it is unclear if the effect of NO is on the delivery of substrate by regulating blood flow or if it modifies insulin action in the tissues directly. This proposal will address blood blow, glucose uptake in skeletal muscle as well as the insulin signalling pathway in eNOS and nNOS knockout mice, and in rats infused with L-NMMA systemically as well as intracranially. It is designed to test the following hypotheses: 1) NOS activity and NO production play an important role in regulating skeletal muscle blood flow in response to insulin. 2) NOS activity regulates glucose uptake by skeletal muscle. 3) NOS activity modulates insulin action in tissues. Thus the experiments detailed in this application will enable us to understand insulin resistance in greater detail, and help guide the development of future therapeutic strategies. In addition, these experiments will allow the PI to be well trained in research techniques, and together with the career development plan result in the development of an independent research scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF INSULIN GENE EXPRESSION IN LIVER CELLS Principal Investigator & Institution: Ozcan, Sabire; Molecular/Cellula/Biochemistry; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Transcriptional regulation plays an important role in determining tissue specificity and every tissue is characterized by a set of specific transcription factors. In the pancreas, the major transcription factor that restricts insulin gene expression to the pancreatic beta cells is the homeodomain protein Pdx-1. Insulin production is essential for maintaining glucose homeostasis and defects in glucoseregulated insulin gene transcription result in diabetes. We have recently discovered that glucose regulates insulin gene expression in beta cells by hyperacetylation of histone H4. Interestingly, in liver cells where the insulin gene is transcriptionally silent, no significant histone acetylation is associated with the insulin gene promoter. However, introduction of Pdx-1 into liver cells caused increased histone H4 acetylation at the normally silent insulin gene promoter in a glucose-dependent manner and stimulated insulin production. Based on these data, we hypothesize that introduction of Pdx-1 into liver cells activates the normally silent insulin gene in response to high levels of glucose by increasing histone H4 acetylation. The major goal of this proposal is to understand how introduction of Pdx-1 into the liver cells stimulates the transcription of the

Studies

69

normally silent insulin gene, by addressing the following questions: 1. Does introduction of Pdx-1 into liver cells cause glucose-regulated changes in histone modification, at the normally silent insulin gene locus? 2. Does Pdx-1 change histone H4 acetylation levels in liver cells by recruiting co-activators or co-repressors to the insulin gene promoter in a glucose-dependent manner? 3. Does the introduction of the beta-cell specific transcription factor Ribe3b1 into the liver cells cause changes in histone modification as observed with Pdx-1? Understanding of how Pdx-1 stimulates the transcription of the normally silent insulin gene in liver cells, will facilitate the development of liver cell lines that can produce insulin in a glucose-dependent manner. The development of such non-beta cell lines will be important for the treatment of type I and as well as type II diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION COACTIVATORS

OF

INSULIN

GENE

TRANSCRIPTION

BY

Principal Investigator & Institution: Thomas, Melissa K.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Scanned from the applicant's description) Diabetes mellitus affects over 16 million individuals in the United States, resulting in substantial costs in morbidity, mortality, and health care expenditures. Current treatment regimens for diabetes mellitus do not normalize insulin production and/or action efficiently enough to restore normal glucose metabolism and prevent major vascular and neurologic complications of hyperglycemia. One approach to identify novel treatment strategies for diabetes mellitus is to study the regulation of insulin production and the molecular defects that lead to relative or absolute insulin deficiency. An increasing number of transcriptional regulators important for the development of the pancreas and/or the regulation of glucose-responsive insulin gene transcription are targets of mutations in individuals with maturity-onset diabetes of the young (MODY) or type 2 diabetes mellitus. Disrupting the functions of pancreatic beta-cell transcription factors may alter the regulation of islet cell mass, beta-cell function, or insulin gene transcription. Transcription factors essential for pancreatic development or for differentiated beta-cell function, including the regulation of insulin gene transcription, are candidate diabetes genes. We have identified a novel PDZ-domain protein, designated Bridge-1, that interacts with E2A transcription factors as a coactivator of insulin gene transcription. The proposed studies are designed to test the hypothesis that Bridge-1 is an important regulator of transcriptional activation of the insulin gene and a modulator of the function of key transcription factors and coactivators in pancreatic beta cells. To address this hypothesis, we propose the following specific alms: 1) to characterize Bridge-1 regulation of insulin gene transcription via protein-protein interactions in pancreatic beta cells, and 2) to determine whether overexpression of the coactivator Bridge-1 or a Bridge-1 transactivation mutant in pancreatic beta cells of transgenic mice alters insulin gene expression or the normal development of the endocrine pancreas. Because Bridge-1 appears to be an important transcriptional regulator of insulin gene expression we propose that it may be a promising candidate gene contributing to susceptibility for the development of type 2 diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

70

Insulin

•

Project Title: ROLE OF FORKHEAD PROTEINS IN INSULIN ACTION Principal Investigator & Institution: Accili, Domenico; Professor of Medicine; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-JAN-2001; Project End 31-DEC-2005 Summary: The mechanism of insulin action is a central question in biology with important ramifications into many areas of human disease, including diabetes, obesity, atherosclerosis and hypertension. Studies of the nematode Caenorhabditis Elegans have provided important insight into insulin action. In this simple metazoan, mutations of the insulin/IGF-1 receptor homologue Daf-2 gene prolong life span, decrease metabolic activity and increase fat accumulation. This characteristic stage, referred to as the dauer stage, can be rescued by mutations of the Daf-16 gene. This suggests that Daf-16 is a negative regulator of insulin/IGF-1 receptor signaling in C. Elegans. Daf-16 encodes a forkhead transcription factor. The investigators have shown that FKHR, the closest mammalian homologue of Daf-16, is an insulin-regulated transcription factor. In hepatocytes, insulin phosphorylates FKHR on at least three different amino acid residues through a hierarchical cascade initiated by the serine-threonine kinase, Akt. Insulin-dependent phosphorylation inhibits the ability of FKHR to stimulate transcription of prototypic insulin-responsive genes like PEPCK and IGFBP-1, in addition to genes that regulate apoptosis. Based on the tissue distribution of the three mammalian Fkhr genes in mice (Fkhr, FkhrII, Afx), as well as their seemingly different phosphorylation patterns, the investigators propose to test the hypothesis that FKHR mediates insulin action in liver and beta cells. There are two specific aims in this proposal. In aim 1, the investigators will address the role of FKHR in insulin-dependent glucose production in vitro. The investigators will first ask whether hepatic glucose production can be regulated by introducing dominant negative or constitutively active mutant FKHRs into hepatocytes from either normal mice or insulin receptor-deficient mice. Next the investigators will address whether differences in the phosphorylation patterns of renal and hepatic FKHR proteins can account for the tissue-specific ability of insulin to suppress hepatic, but not renal gluconeogenesis. In aim 2, the investigators will introduce null alleles of FKHR in mice using conditional mutagenesis and ask whether selective ablation of FKHR in liver and/or beta cells can rescue diabetes in insulin resistant mice by reducing glucose output or preventing beta cell apoptosis. Conversely, the investigators will attempt to induce diabetes in mice by means of a constitutively active mutant FKHR, generated through a novel "knock-in" approach. These investigations will shed new light onto the mechanisms by which insulin resistance causes hyperglycemia, and disclose new approaches to the treatment of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ROLE OF GLYCOGEN SYNTHASE KINASE 3 IN TYPE 2-DIABETES Principal Investigator & Institution: Henry, Robert R.; Chief; Veterans Medical Research Fdn/San Diego Foundation of San Diego San Diego, Ca 92161 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-JUL-2005 Summary: Major characteristics of type 2 diabetes include impairments of insulin signaling and skeletal muscle glucose utilization, manifested by defects in IRS-1 associated PI3-kinase activity and the activation state of glycogen synthase (GS). The activity of GS is controlled, in part, through phosphorylation by glycogen synthase kinase-3 (GSK3), which inactivates GS. GSK3 can also phosphorylate IRS-1, reducing its function. We have shown that GSK3 activity is elevated in muscle from Type 2 diabetic

Studies

71

subjects. The hypothesis to be tested in this project is that elevations of GSK3 contribute to insulin resistance. Specific aim 1 will be to determine the role of GSK3 in regulation of insulin signaling. We will delineate the impact of GSK3 manipulations on insulin signaling in cultured human skeletal muscle cells and assess correlations between GSK3 expression and insulin-stimulated IRS-1 associated PI3-K in skeletal muscle biopsies. Specific aim 2 will determine what factors of the in vivo diabetic environment lead to acquired defects of GSK3 in diabetic muscle. Human skeletal muscle cells from nondiabetic and diabetic subjects will be grown in culture and the metabolic conditions (glucose, insulin, free fatty acids, TNFalpha) selectively manipulated to recreate the diabetic metabolic phenotype and assess the impact on GSK3 expression. Specific aim 3 will obtain more specific information about the direct involvement of GSK3 in muscle cell metabolism and insulin action by use of overexpression, targeted reduction with antisense oligonucleotides, and specific inhibitors of GSK3 in muscle cells, to determine whether alterations in GSK3 can influence muscle metabolism. Specific aim 4 will fully characterize the relationship between GSK3 expression and activity in skeletal muscle and adipose tissue biopsies and in vivo insulin action and glucose disposal of lean nondiabetic, obese non-diabetic and obese Type 2 diabetic subjects. GSK3 expression and activity will be compared between muscle and fat from the same subjects. Besides basic mechanistic information about insulin signaling, these studies will reveal whether GSK3 plays a key role in the pathogenesis of Type 2 diabetes, increasing our understanding of the causes and possible treatments of insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROSIGLITAZONE IN POLYCYSTIC OVARY SYNDROMEN Principal Investigator & Institution: Cataldo, Nicholas A.; Assistant Professor of Obstetrics and Gy; Gynecology and Obstetrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (Adapted from applicant's description): Polycystic ovary syndrome (PCOS) is a disorder affecting about 5% of reproductive-age women characterized by anovulation and excess production of androgens by the ovary. Anovulation causes menstrual irregularity and infertility, while excess androgens cause unwanted hair growth and may promote acne. Traditional treatments for PCOS have consisted of medication to stimulate ovulation if fertility is desired, or medication to suppress or block androgents or restore regular menstrual cycles if fertility is not an immediate goal, but these treatments are often mutually exclusive PCOS is frequently associated with a common metabolic disorder, insulin resistance, and like insulin resistance alone carries an increased risk of non-reproductive health problems such as the development of diabetes or atherosclerosis. Insulin resistance leads to excessive insulin secretion, and this may stimulate the ovary to hypersecrete androgens. In the last few years, published reports have described the treatment of PCOS with insulin sensitizers, medications developed to treat diabetes which can improve insulin resistance. These drugs can improve the hormonal abnormalities in PCOS and in some cases can restore regular menses and/or ovulation. Of the two marketed drugs tested to date, metformin has not been consistently effective, while troglitazone is effective but has been found to have an unacceptable risk of liver toxicity. This project will study rosiglitazone, a newly approved drug closely related to troglitazone in structure and action but without apparent toxicity, in an open-label, Phase II format. Subjects with PCOS wiII have insulin resistance identified by dynamic testing using the octreotide insulin suppression test, and after further evaluation of provoked insulin secretion will receive rosiglitazone daily in one of three doses for 12 weeks. Insulin resistance and insulin

72

Insulin

secretion, glucose tolerance, serum total and free testosterone, LH, and circulating lipids will be measured on rosiglitazone and compared to subjects' pretreatment values. The occurrence of ovulation will be evaluated by weekly serum progesterone levels. The dose of rosiglitazone and the time needed for its effect to develop will be determined. Associations between effects on metabolic parameters and effects on reproductive ones will be sought. The hypothesis of this study is that rosiglitazone can improve insulin sensitivity and lower circulating insulin, and thereby restore ovulation as well as correct elevated LH and testosterone. Rosiglitazone is potentially an appropriate and beneficial treatment for all women with PCOS and insulin resistance regardless of goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SIGNALING PATHWAYS IN INSULIN ACTION Principal Investigator & Institution: Saltiel, Alan R.; Professor of Medicine and Physiology; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Almost 16 million people in the US are thought to be afflicted, a third of whom are undiagnosed. Insulin resistance is recognized as a defined characteristic trait of the disease, by the inability to respond to normal circulating levels of insulin. The primary lesion in this state involves defects in the uptake and storage of glucose in muscle and fat cells. Targeting these defects holds the key to the development of new therapeutic approaches. However, understanding the specific lesions that cause insulin resistance in patients with type 2 diabetes will first require a better grasp of the cell biology of insulin action. To this end, the molecular events involved in the regulation of glucose uptake by insulin will be investigated, with special attention to the underlying basis for the specificity of actions of the hormone. Recent data has revealed the activation of a novel tyrosine phosphorylation pathway that is localized to discrete domains of the plasma membrane called lipid rafts. Aim 1 will evaluate the role of the primary insulin receptor substrate in this pathway, the protooncogene c-cbl. Mutations in cbl and its binding partners crk and C3G will be introduced to determine whether this pathway plays an essential role in insulin action. In Aim 2 the adapter protein CAP that enables the receptor to phosphorylate cbl will be studied. Analysis of the structure/function relationship of CAP will depend on the development of deletion and chimeric mutants, in order to further evaluate the importance of the pathway. Aim 3 will focus on the new concept that there are two pools of insulin receptor that are spatially segregated in the plasma membrane, each linked to different signaling pathways. Finally, the physiological role of the pathway will be studied in Aim 4 by the targeted disruption of the CAP gene in mice in a tissue-specific manner. Together, these approaches will allow for the evaluation of the importance of this novel pathway in insulin action, setting the stage for future investigations into its potential role in the development of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SOCS PROTEINS - INHIBITORS OF HEPATIC INSULIN RECEPTORS Principal Investigator & Institution: Mooney, Robert A.; Professor; Pathology and Lab Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Pro-inflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFa) are elevated in

Studies

73

obesity and type 2 diabetes and have been shown to antagonize insulin action in cell and animal models. While TNFa has been strongly implicated in obesity-dependent insulin resistance in skeletal muscle and adipose tissue, the role of IL-6, TNFa, and IL-1 in hepatic insulin resistance is less understood. Recently, a family of eight cytokineinduced tyrosine kinase inhibitors called Suppressors of Cytokine Signaling (SOCS) have been described. We have now demonstrated in HepG2 cells that IL-6 induces expression of SOCS-3 in a temporal pattern that parallels its inhibitory effects on insulin receptor (IR) signal transduction. Ectopically expressed SOCS-3 also inhibits IR signaling in HepG2 cells. Importantly, when induced by IL-6, endogenous SOCS-3 complexes with the IR in these cells. The objective of this proposal is to develop experimental support for the hypothesis that cytokine-induced SOCS proteins (SOCS-3 being the prototype) are antagonists of IR signal transduction in the liver and contribute to insulin resistance. With the long term goal of defining the mechanism by which cytokines contribute to insulin resistance and type 2 diabetes, the following aims will be pursued: Specific Aim #1: Characterize the effect of cytokine (IL-1, IL-6 and TNFa)dependent induction of SOCS-3 on insulin receptor signal transduction in primary hepatocytes, HepG2 cells, and mouse models. Determine if SOCS-3 expression is necessary and/or sufficient for IL-6-dependent inhibition of IR signaling (using RNAi, dominant negative mutants, and transcriptional repression) in cells and animal models. Specific Aim #2: Define the molecular mechanism by which SOCS-3 inhibits IR signal transduction. Deletion and point mutations of SOCS-3 and IR will be constructed and their impact on SOCS-IR interactions and IL-6-mediated IR inhibition will be examined using structure-function analysis. This project focuses on the poorly understood antagonism by cytokines (especially IL-6) of IR signaling in the liver. SOCS proteins may potentially be an important contributors to regulation of insulin signaling and a possible target for therapeutic intervention in the treatment of insulin resistance and type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE OF IRS PROTEINS IN INSULIN RESISTANCE Principal Investigator & Institution: Shoelson, Steven E.; Senior Investigator; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 31-MAR-2003 Summary: Adapted from applicant's abstract): Insulin controls systemic metabolism by regulating glucose uptake, the synthesis and storage of glycogen and fat, and protein and DNA synthesis. Insulin=s cellular effects are mediate by the insulin receptor (IR) and its substrates. The known number of insulin receptor substrates (IRS proteins) has recently expanded to four, IRS-1, -2, -3, and -4. The activated IR phosphorylates IRS proteins directly. Tyrosine-phosphorylated IRS proteins bind and activate SH2 domain enzymes, including the PI 3-kinase, the phosphatase SHP-2, and the Grb2/Sos complex, to amplify and propagate insulin signals into cells. Insulin resistance- the ability of key targets (muscle and fat) to respond to insulin- is considered t be the initiating step in the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM). Insulin resistance is also associated with common disease states such as hypertension, atherosclerosis, aging, obesity, and polycystic ovarian disease. Recent findings suggest that Ser/threonine phosphorylation of IRS proteins may cause insulin resistance in cells and in vivo. Hyperglycemia, hyperinsulinemia, TNF and leptin could influence insulin sensitivity through this mechanism. The proposed studies will provide a structural basis for understanding the early events in insulin action and test hypotheses that relate insulin resistance and Ser/Thr phosphorylation of IRS proteins. Specifically, we will (1)

74

Insulin

Determine high resolution structures of IRS protein homology domains (the approximately 270 residue region common to IRS proteins that encompasses the PH and PTB domains), (2) Determine physiological binding partners for the IRS-1, -2, -3, and -4 PH and PTB domains, (3) Determine high resolution structures of full-length IRS proteins (IRS-3 is being attempted first, but IRS-1 is planned, as well), and (4) Use IRS structures to analyze potential mechanisms of insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUBSTRATES AND INSULIN RECEPTOR ENDOCYTOSIS Principal Investigator & Institution: Najjar, Sonia M.; Associate Professor; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 31-JAN-2004 Summary: Impaired insulin action, or insulin resistance, is a hallmark of Non-InsulinDependent Diabetes Mellitus (NIDDM). Because insulin resistance is a major factor in the pathogenesis of NIDDM, understanding the mechanisms of insulin resistance has potential implications in identifying novel means to improve insulin sensitivity in individuals predisposed to NIDDM. Insulin binding to its receptor activates the tyrosine kinase of the receptor to cause phosphorylation of the receptor and of other substrates, such as ppl20, a plasma membrane glycoprotein in the hepatocyte. pp120 is phosphorylated on Ser503 in the intracellular domain by cAMP-dependent kinase in the absence of insulin, and this phosphorylation is required for its phosphorylation on Tyr488 by the insulin receptor kinase in response to insulin. The role of ppl20 in insulin action is not well understood. pp120 expression in cultured cells was correlated with increased rate of insulin clearance from the medium through a mechanism of receptormediated endocytosis, suggesting that pp120 is important in the process of insulin clearance from the portal circulation. In contrast, expression of phosphorylationdefective pp120 isoforms (truncated and the Y488F and S503A site-directed mutants) did not increase receptor-mediated insulin internalization, suggesting that the effect of p120 on insulin endocytosis depends on its phosphorylation state. Immunofluorescence and biotin-labeling studies suggested that pp120 exerts its effect by undergoing receptormediated internalization in response to insulin. Thus, it appears that pp120 takes part in a complex of proteins that target the insulin receptor to endocytosis vesicles. The complex formation between pp120, at Tyr488, and the insulin receptor, at Tyr960 of its juxtamembrane domain, appears to be mediated by intracellular proteins. We herein propose to identify these proteins. Additionally, we propose to address the role of ppl20 in the mechanism of insulin action in vivo. To this end, we have generated a transgenic mouse overexpressing a phosphorylation-defective S503A isoform of ppl20 in liver. The transgenic line will address whether expression of a phosphorylation-defective pp 120 is associated with a blunted ability to remove excess insulin from the portal circulation, causing peripheral hyperinsulinemia. Since hyperinsulinemia leads to receptor downregulation on target tissues, it is usually associated with insulin resistance. These proposed studies should provide novel insights into a potential mechanism of hyperinsulinemia, insulin resistance and diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE 4 CORNERS BREAST AND ENDOMETRIAL CANCER STUDY Principal Investigator & Institution: Baumgartner, Kathy B.; PhD; Internal Medicine; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131

Studies

75

Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: (Adapted from Applicant's Abstract) The incidence of breast and endometrial cancers varies almost three-fold between non-Hispanic white populations and Native American and Hispanic populations living in the 4-Corners area of the United States (Arizona, New Mexico, Colorado, and Utah). Interestingly, although American Indian and Hispanic women have higher prevalences of many risk factors for breast and endometrial cancer identified in non-Hispanic white women (e.g., obesity, low levels of vigorous physical activity, low intakes of fruits and vegetables, high rates of insulin resistance) they have lower cancer incidence rates. In this study the investigators focus on the metabolic factors of obesity/weight changes and indicators of insulin status as they relate to breast and endometrial cancers. Obesity is associated both with estrogen and insulin by two interrelated disease pathways. Insulin may influence cancer risk directly through its effects on insulin-like growth factor (IGF) and its binding proteins (IGFBPs) and well as indirectly through its effect on estrogen levels. The investigators propose focusing on the insulin pathway because of the high levels of insulin pathway dysfunction in this population. A multi-center case-control study is proposed that targets women living in the 4-Corners area; the study will consist of a 2.5 hour in-person interview and a blood draw. Over a three-year case ascertainment period, the study will enroll 3000 breast cancer cases, 450 endometrial cancer cases and 3000 controls, half of whom will be Hispanic/Native American and half of whom will be non-Hispanic white women between the ages of 25 and 79. Molecular variants of genes that influence obesity and insulin (androgen receptor gene (AR), vitamin D receptor gene(VDR), insulin receptor (ADRB3)) will be examined both independently and in conjunction with metabolic factors to determine differences in genetic susceptibility in the population. Because of the diverse population (Hispanics, Native American, and non-Hispanic white women), the investigators propose to evaluate ethnic background and genetic admixture in relationship to gene markers, environmental factors, and breast and endometrial cancer risk. Genetic admixture (Ameridian to European genetic mixture) is a novel and innovative way to study the continuum of ethnic diversity. C-peptide, glycosylated hemoglobin, IGF-1, and IGFBP3 will be evaluated with respect to breast and endometrial cancer in a subset of women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE EFFECTS OF INSULIN ON THE MICROVASCULATURE Principal Investigator & Institution: Barrett, Eugene J.; Professor; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001; Project Start 15-APR-2001; Project End 31-MAR-2006 Summary: Historically, two parallel lines of evidence have developed linking the regulation of muscle blood flow and muscle metabolism. One originates with clinical investigations examining the action of insulin- on bulk muscle (limb) blood flow and its impairment with insulin resistance. These studies have generated controversy regarding the physiological and clinical relevance of insulin's actions on total blood flow. The second line of evidence originates with more basic studies of the microvasculature and its neurohumoral regulation in muscle. The laboratory of the PI and the Co-investigators began a collaboration 5 years ago directed at developing new methods to study micro-vascular flow distribution within skeletal muscle "in-vivo". Sufficient preliminary data are now available to support using several approaches to measuring blood flow distribution in skeletal muscle in-vivo. These methods include measurement of the metabolism of exogenously added 1-methylxanthine to 1methylurate by capillary xanthine oxidase, laser Doppler flowmetry (LDF), and

76

Insulin

contrast-enhanced ultrasonography (CEU). With these techniques, we propose to address three Aims: First to determine in vivo the time course and dose-response of capillary recruitment by insulin in normal sedentary, in exercise-trained and insulinresistant rats. Second, we will define in human skeletal muscle the response of the microvasculature to insulin and feeding and whether these responses are altered by DM2, obesity and hypertension. The relationship of the microvascular and metabolic actions of insulin will be correlated to ascertain potential relationships. These studies will test the general hypothesis that insulin at physiologically relevant concentrations and exposure times, regulates skeletal muscle capillary recruitment, preferentially directing flow through a "nutritive" capillary network and that this can occur even in the absence of changes in total blood flow to a limb. Finally, we will examine the mechanism and anatomic pathways of insulin's microvascular action by testing a series of hypotheses relating to whether insulin vascular action requires glucose metabolism in muscle, whether insulin redirects flow away from connective tissue vessels to vessels in close apposition to myocytes and finally whether insulin's microvascular action differ from those of other vasodilators. In the latter studies we will test directly whether augmenting or diminishing muscle capillary recruitment affects the simultaneously measured action of insulin to promote glucose uptake by skeletal muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE FUNCTION OF PHOSPHOLIPASE A2 IN ISLET BETA-CELLS Principal Investigator & Institution: Ma, Zhongmin A.; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Defective or abnormal insulin secretion by islets in response to glucose results in diabetes mellitus (DM). Glucose-stimulated hydrolysis of arachidonic acid (AA) from membrane phospholipids has been suggested to play a role in glucose-stimulated insulin secretion from beta-cells. Certain receptor-mediated insulin-secretagogues, such as glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin-8 (CCK-8) also stimulate release of AA by activating islet phospholipase A2 (PLA2). Our long-term objectives are to understand the mechanism of PLA2 signaling pathway in insulin secretion and to characterize the regulation of PLA2 and its interaction with other components involved in the insulin secretion machinery in beta-cells. A Ca2+ -independent PLA2 (iPLA2) has been cloned from rat and human islets, iPLA2 is dominantly expressed in islet beta-cells and its catalytic activity is stimulated by ATP, a well-known signal in glucose-stimulated insulin secretion. Specific inhibition of iPLA2 with bromoenol lactone (BEL) leads to the suppression of both glucose-stimulated insulin secretion and AA release. Expression of iPLA2 in insulinoma INS-1 cells significantly increases glucose sensitivity of INS-1 cells, which is further enhanced by increasing cAMP levels. Our hypothesis is that iPLA2 is one component of the beta-cell fuel-sensing apparatus that constitutes an underlying link among glycolytic, receptor signaling, and membrane phospholipolytic pathways to participate in both nutrient and non-nutrient insulin-secretagogue stimulated insulin secretion. Aim 1 is to examine the function of iPLA2 in glucose-stimulated insulin secretion in islets by overexpressing and underexpressing iPLA2 in freshly isolated islets. Aim 2 is to characterize the ATP-regulated iPLA2 activation and translocation from the cytosol to cellular membranes of beta-cells by mutagenesis of ATP binding domain of iPLA2 and GFP-fusion protein analyses. Aim 3 is to characterize the interaction of iPLA2 with cAMP/PKA by pharmacological inhibition and phosphorylation analyses. Aim 4 is to determine the role of iPLA2 in glucose sensing in

Studies

77

vivo in iPLA2-knockout mice and in the islets isolated from iPLA2-/- mice. The proposed studies should contribute significantly to our understanding of the biological importance of iPLA2 in islet beta-cells and will lead to the elucidation of mechanisms by which to increase insulin secretion by beta-cells in response to insulin secretagogues for prevention of type 2 DM and for developing high-quality insulin secreting beta-cells for cell therapy of type 1 DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE PATHOPHYSIOLOGY OF TYPE 2 DIABETES IN ADOLESCENTS Principal Investigator & Institution: Brickman, Wendy J.; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-JAN-2005 Summary: (adapted from the application) In adults, type 2 diabetes represents a group of polygenic disorders with abnormalities in insulin sensitivity, insulin secretion, and hepatic glucose production. Recently, there have been increased reports of what appears to be type 2 diabetes in the pediatric population. This increase in type 2 diabetes in children has occurred amidst an environment of increasing insulin resistance, as noted by 1) the pubertal stage of many affected individuals, 2) the parallel increase in obesity within the pediatric population, 3) the parallel increase in sedentary lifestyle features, and 4) the frequent presence of acanthosis nigricans. However, all individuals with insulin resistance do not have type 2 diabetes. Little data is available on the pathophysiology of impaired glucose tolerance and type 2 diabetes in children and adolescents. In order to prove that type 2 diabetes in adolescents is characterized by severe insulin resistance and defects in B-cell function, adolescents with Type 2 diabetes followed at Children's Memorial Hospital will undergo a thorough history, physical examination, an oral gluocse tolerance and, in a subset of participants, a frequently sampled intravenous glucose tolerance test. In order to prove that adolescents with acanthosis nigricans and varying degrees of glucose tolerance are characterized by severe insulin resistance and defects in B-cell function, a group of adolescents with acanthosis nigricans will be recruited. Each will have a thorough history and targeted physical, and an oral glucose tolerance test to assess insulin sensitivity, insulin secretion, and glucose tolerance. A subset of these will also undergo a modified IVGTT as well. In order to prove that adolescents with insulin resistance have evidence of risk factors for later cardiovascular disease, a group of individuals with low insulin sensitivity will have cardiovascular studies to evaluate for pediatric antecedents of cardiovascular disease. A better understanding of the pathophysiology of type 2 diabetes and its development in adolescents, will enable us to predict which preventive and therapeutic interventions will be successful in hopes of improving the morbidity and mortality associated with type 2 diabetes and/or severe insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE ROLE OF PPARGAMMA EXPRESSION ON INSULIN ACTION Principal Investigator & Institution: Hevener, Andrea L.; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-DEC-2004 Summary: (provided by applicant) Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus. The PPARgamma nuclear receptor is the target of Thiazolidinediones (TZD), a class of anti-diabetic drugs known to ameliorate insulin resistance. Despite the known action of TZDs to improve insulin sensitivity, many

78

Insulin

aspects of PPARgamma biology remain relatively unclear. In this application we plan to utilize gene knockout technology to elucidate the physiologic and cellular mechanisms of PPARgamma biology relating to insulin action and glucose homeostasis. Previous studies from our laboratory have shown that animals heterozygous for a PPAR gene deletion (PPARgamma+/-) demonstrate enhanced insulin sensitivity in muscle and liver. This led us to hypothesize that the PPARgamma receptor and its natural ligands normally serve to dampen insulin action. We believe that PPARgamma gene deletion releases this dampening effect leading to heightened insulin sensitivity. Since the PPARgamma+/-mice display enhanced insulin sensitivity, (1) we will test the hypothesis that when crossed into genetically insulin resistant animals, the insulin resistance phenotype will be rescued. While it is known that TZDs improve the ability of insulin to stimulate glucose disposal, the site of TZD action remains unknown. (2) To assess the differential role of PPARgamma receptor expression in fat vs. muscle, our laboratory has used the Cre-Lox system to create animals with a PPARgamma gene deletion in either skeletal muscle (MCK-Cre mice), or adipose tissue (aP2-Cre mice). The phenotype of these animals will be studied in vivo and in vitro, with or without perturbations including: a) TZD treatment and b) high fat feeding. In summary, in this application we propose to utilize the techniques of mouse genetics combined with a variety of in vivo and in vitro studies to elucidate the role of PPARgamma nuclear receptors in whole body, skeletal muscle, and adipose tissue metabolism. We feel that the findings from the proposed investigations will improve our general understanding of insulin resistance and offer potential insights into new therapeutic modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE TRANSDUCTION

ROLE

OF

SPHINGOLIPIDS

IN

INSULIN

SIGNAL

Principal Investigator & Institution: Summers, Scott A.; Assistant Professor; Biochem and Molecular Biology; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: The peptide hormone insulin stimulates glucose uptake and storage in skeletal muscle while simultaneously inhibiting glucose efflux from the liver. In certain pathological conditions, most notably type II diabetes mellitus, these tissues become resistant to insulin's effects, leading to abnormalities in glucose homeostasis. Determining the signal transduction events that link insulin's arrival at the cell surface to its numerous physiological responses is critical for a complete understanding of the development of insulin resistance. Membrane lipids have emerged as important regulators of hormone action. For example, phosphoinositide products of PI3-kinase are critical for the anabolic effects of insulin. Conversely, the sphingomyelin derivative ceramide, which is elevated in diabetic tissues, antagonizes insulin-stimulation of glucose uptake by preventing PI3-kinase from activating downstream signaling molecules. Moreover, circulating factors implicated in diabetic onset, such as free fatty acids or tumor necrosis factor-alpha, promote ceramide biosynthesis, suggesting that aberrant ceramide accumulation might contribute to the development of insulin resistance. Interestingly, preliminary data obtained in our laboratory indicate that another sphingolipid, sphingosine 1- phosphate, may prevent the ceramide effect on insulin signaling. The project proposed herein will evaluate the molecular mechanisms underlying ceramide and sphingosine 1-phosphate regulation of insulin action. First, we will test several hypothetical mechanisms by which ceramide regulates PI3-kinase dependent signaling. Second, we will evaluate the effectiveness of sphingosine 1phosphate as both an antagonist of ceramide signaling and a positive regulator of

Studies

79

normal insulin action. Results obtained, in addition to providing insight into the contribution of sphingolipids to basic hormonal signal transduction, could have significant implications on our understanding and treatment of type II diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF THE AKT/PKB SIGNALING IN INSULIN ACTION Principal Investigator & Institution: Birnbaum, Morris J.; Professor and Investigator; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 15-FEB-2000; Project End 31-JAN-2005 Summary: Type II Diabetes Mellitus is one of the most common diseases in the Western world, with prevalence ranging from 10-50% in older populations. An integral component of Type II diabetes mellitus is insulin resistance, i.e. an inability of maximal concentrations of the hormone to stimulate appropriate muscle glucose transport and other physiological response. A plausible strategy leading to the development of novel in insulin-sensitizing drugs begins with the systematic analysis of the insulin signaling. After over 20 years of intensive research in the pursuit of relevant serine/threonine protein kinases, Akt/PKB has emerged as a major candidate mediator of insulin's regulation of important metabolic targets. Akt/PKB has emerged as a major candidate mediator of insulin's regulation of important metabolic targets. Akt/PKB is a fairly ubiquitous serine/threonine protein kinase, whose activity depends on the lipid products of phosphatidylinositol 3'-kinase, an enzyme known to be required for virtually all of the metabolic actions of insulin. Though this a rapidly evolving field, at the present time the bulk of evidence suggests that Akt/PKB almost certainly mediates insulin's and IGF1's effects to time the bok of evidence suggests that Akt/PKB almost certainly mediates insulin's and IGF1's effects to antagonize apoptosis, probably contribute to insulin's stimulation of protein, glycogen and triglyceride synthesis, and possibly is involved in insulin's activation of glucose transport. Moreover, there is definitive data demonstrating that Akt/PKB represents an obligate intermediate in an insulin receptor-initiated pathway in the nematode, C. elegans. The primary goals of the studies describes in this grant proposal are to more carefully define the role of Akt/PKB in physiologically relevant insulin signaling, and to understand in more detail the intermediates both between the insulin receptor and Akt/PKB, as well as intervening between the latter kinase and biological outputs. These goals will be accomplished via two distinct strategies: 1) the evaluation of candidate proteins suspected or implicated in the Akt/PKB pathway, and several genetic and biochemical screens for new intermediates, and 2) a careful analysis of the phenomenon of "insulin specificity" in cultured murine adipocytes, in which activation of Akt/PKB parallels that of glucose transport. Insulin specificity, in the context employed here, refers to the observation that only insulin, but not other growth factors such as PDGF, stimulates glucose transport, in spite of both sets of agonists activating the same early steps in signaling with equal efficacy. It is anticipated that, through these studies, a much deeper understanding will be obtained concerned the critical intracellular events which mediate insulin's regulation of essential metabolic functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

80

Insulin

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “insulin” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for insulin in the PubMed Central database: •

[beta]-Arrestin 1 down-regulation after insulin treatment is associated with supersensitization of [beta]2 adrenergic receptor G[alpha]s signaling in 3T3-L1 adipocytes. by Hupfeld CJ, Dalle S, Olefsky JM.; 2003 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140914

•

13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS). by Lu D, Mulder H, Zhao P, Burgess SC, Jensen MV, Kamzolova S, Newgard CB, Sherry AD.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122412

•

1-Phosphatidylinositol 3-Kinase Activity is Required for Insulin-Stimulated Glucose Transport But not for RAS Activation in CHO Cells. by Hara K, Yonezawa K, Sakaue H, Ando A, Kotani K, Kitamura T, Kitamura Y, Ueda H, Stephens L, Jackson TR, Waterfield MD, Kasuga M.; 1994 Aug 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44411

•

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. by Bergerot I, Ploix C, Petersen J, Moulin V, Rask C, Fabien N, Lindblad M, Mayer A, Czerkinsky C, Holmgren J, Thivolet C.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20771

•

A dominant-negative mutant of mSOS1 inhibits insulin-induced Ras activation and reveals Ras-dependent and -independent insulin signaling pathways. by Sakaue M, Bowtell D, Kasuga M.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231974

•

A Function for Phosphatidylinositol 3-Kinase [beta] (p85[alpha]-p110[beta]) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction. by Roche S, Downward J, Raynal P, Courtneidge SA.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109293

•

A novel glucose-responsive element in the human insulin gene functions uniquely in primary cultured islets. by Sander M, Griffen SC, Huang J, German MS.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21682

3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

Studies

81

•

A phosphatidylinositol 3-kinase /Akt /mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. by Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, Donner DB.; 2001 Apr 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31887

•

A Region of the Insulin Receptor Important for Ligand Binding (Residues 450-601) is Recognized by Patients' Autoimmune Antibodies and Inhibitory Monoclonal Antibodies. by Zhang B, Roth RA.; 1991 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52820

•

A Role for Protein Kinase B[beta]/Akt2 in Insulin-Stimulated GLUT4 Translocation in Adipocytes. by Hill MM, Clark SF, Tucker DF, Birnbaum MJ, James DE, Macaulay SL.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84835

•

A Transgene Coding for a Human Insulin Analog has a Mitogenic Effect on Murine Embryonic [beta] Cells. by Vincent MT, Carroll RJ, Hammer RE, Chan SJ, Guz Y, Steiner DF, Teitelman G.; 1995 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41493

•

Acceleration of type 1 diabetes mellitus in proinsulin 2 --deficient NOD mice. by Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, VallonGeoffroy K, Morin J, Laloux V, Lehuen A, Carel JC, Jami J, Muller S, Boitard C.; 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153768

•

Activation of mitogen-activating protein kinase by glucose is not required for insulin secretion. by Khoo S, Cobb MH.; 1997 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20824

•

Activation of Phosphatidylinositol 3-Kinase by Insulin. by Ruderman NB, Kapeller R, White MF, Cantley LC.; 1990 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53485

•

Activation of Reg gene, a gene for insulin-producing [beta]-cell regeneration: Poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. by Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ, Ikeda T, Nakagawa K, Unno M, Matsuno S, Okamoto H.; 2001 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14542

•

Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1[alpha] and VEGF. by Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP.; 2002 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150907

•

ADD-1 provides major new insight into the mechanism of insulin action. by Flier JS, Hollenberg AN.; 1999 Dec 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33942

82

Insulin

•

Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulinstimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes. by Sharma PM, Egawa K, Gustafson TA, Martin JL, Olefsky JM.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232594

•

Adipose-derived resistin and gut-derived resistin-like molecule --[beta] selectively impair insulin action on glucose production. by Rajala MW, Obici S, Scherer PE, Rossetti L.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151868

•

ADP-Ribosylation Factor 6 Delineates Separate Pathways Used by Endothelin 1 and Insulin for Stimulating Glucose Uptake in 3T3-L1 Adipocytes. by Lawrence JT, Birnbaum MJ.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87251

•

Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine. by Wright JR Jr.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137361

•

Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. by McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125016

•

An eye on insulin. by Bronson SK, Reiter CE, Gardner TW.; 2003 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161434

•

An SH2 Domain-Containing 5[prime prime or minute] Inositolphosphatase Inhibits Insulin-Induced GLUT4 Translocation and Growth Factor-Induced Actin Filament Rearrangement. by Vollenweider P, Clodi M, Martin SS, Imamura T, Kavanaugh WM, Olefsky JM.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116038

•

Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2Kd that stimulates CD8 T cells in insulin-dependent diabetes mellitus. by Wong FS, Moustakas AK, Wen L, Papadopoulos GK, Janeway CA Jr.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122807

•

Analysis of the Genes Involved in the Insulin Transmembrane Mitogenic Signal in Chinese Hamster Ovary Cells, CHO-K1, Utilizing Insulin- Independent Mutants. by Mamounas M, Ross S, Luong CL, Brown E, Coulter K, Carroll G, Englesberg E.; 1991 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51485

•

Anchoring of protein kinase A facilitates hormone-mediated insulin secretion. by Lester LB, Langeberg LK, Scott JD.; 1997 Dec 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25142

•

Antagonistic Effects of a Covalently Dimerized Insulin Derivative on Insulin Receptors in 3T3-L1 Adipocytes. by Weiland M, Brandenburg C, Brandenburg D, Joost HG.; 1990 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53429

Studies

83

•

Anti-Inositolglycan Antibodies Selectively Block Some of the Actions of Insulin in Intact BC3H1 Cells. by Romero G, Gamez G, Huang LC, Lilley K, Luttrell L.; 1990 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53498

•

Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23. by Liu E, Moriyama H, Abiru N, Miao D, Yu L, Taylor RM, Finkelman FD, Eisenbarth GS.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151146

•

APS Facilitates c-Cbl Tyrosine Phosphorylation and GLUT4 Translocation in Response to Insulin in 3T3-L1 Adipocytes. by Liu J, Kimura A, Baumann CA, Saltiel AR.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133825

•

Ascorbic Acid is Essential for the Release of Insulin from Scorbutic Guinea Pig Pancreatic Islets. by Wells WW, Dou C, Dybas LN, Jung C, Kalbach HL, Xu DP.; 1995 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40504

•

Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks. by Schaffer L, Brissette RE, Spetzler JC, Pillutla RC, Ostergaard S, Lennick M, Brandt J, Fletcher PW, Danielsen GM, Hsiao KC, Andersen AS, Dedova O, Ribel U, Hoeg-Jensen T, Hansen PH, Blume AJ, Markussen J, Goldstein NI.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153573

•

Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin. by Pruett W, Yuan Y, Rose E, Batzer AG, Harada N, Skolnik EY.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230402

•

Association of Insulin Receptor Substrate 1 (IRS-1) Y895 with Grb-2 Mediates the Insulin Signaling Involved in IRS-1-Deficient Brown Adipocyte Mitogenesis. by Valverde AM, Mur C, Pons S, Alvarez AM, White MF, Kahn CR, Benito M.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86861

•

Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function. by Ueno H, Kondo E, Yamamoto-Honda R, Tobe K, Nakamoto T, Sasaki K, Mitani K, Furusaka A, Tanaka T, Tsujimoto Y, Kadowaki T, Hirai H.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14806

•

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. by Zhao AZ, Zhao H, Teague J, Fujimoto W, Beavo JA.; 1997 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20350

•

Augmentation of Synthesis of Plasminogen Activator Inhibitor Type 1 by Insulin and Insulin-Like Growth Factor Type I: Implications for Vascular Disease in Hyperinsulinemic States. by Schneider DJ, Sobel BE.; 1991 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52846

84

Insulin

•

Autocrine/Paracrine Role of Insulin-Related Growth Factors in Neurogenesis Local Expression and Effects on Cell Proliferation and Differentiation in Retina. by Hernandez-Sanchez C, Lopez-Carranza A, Alarcon C, de la Rosa EJ, de Pablo F.; 1995 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40897

•

Bridge-1, a Novel PDZ-Domain Coactivator of E2A-Mediated Regulation of Insulin Gene Transcription. by Thomas MK, Yao KM, Tenser MS, Wong GG, Habener JF.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84960

•

Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis. by Dessein PH, Stanwix AE, Joffe BI.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125299

•

Cellular Compartmentalization in Insulin Action: Altered Signaling by a LipidModified IRS-1. by Kriauciunas KM, Myers MG Jr, Kahn CR.; 2000 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86221

•

Cellular effects of phosphotyrosine-binding domain inhibitors on insulin receptor signaling and trafficking. by Giorgetti-Peraldi S, Ottinger E, Wolf G, Ye B, Burke TR Jr, Shoelson SE.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231843

•

Characterization of Insulin-Responsive GLUT4 Storage Vesicles Isolated from 3T3-L1 Adipocytes. by Hashiramoto M, James DE.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85096

•

Chromostatin, a Chromogranin A-Derived Bioactive Peptide, is Present in Human Pancreatic Insulin ([beta]) Cells. by Cetin Y, Aunis D, Bader M, Galindo E, Jorns A, Bargsten G, Grube D.; 1993 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46086

•

c-jun inhibits insulin control element-mediated transcription by affecting the transactivation potential of the E2A gene products. by Robinson GL, Henderson E, Massari ME, Murre C, Stein R.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230364

•

c-Jun Represses the Human Insulin Promoter Activity that Depends on Multiple cAMP Response Elements. by Inagaki N, Maekawa T, Sudo T, Ishii S, Seino Y, Imura H.; 1992 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48382

•

Cloning and Functional Characterization of a Third Pituitary Adenylate CyclaseActivating Polypeptide Receptor Subtype Expressed in Insulin- Secreting Cells. by Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J, Seino S.; 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43433

Studies

85

•

Cloning, Characterization, and Expression of a Novel Zn2 +-Binding FYVE FingerContaining Phosphoinositide Kinase in Insulin-Sensitive Cells. by Shisheva A, Sbrissa D, Ikonomov O.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=83920

•

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity. by Mynatt RL, Miltenberger RJ, Klebig ML, Zemel MB, Wilkinson JE, Wilkison WO, Woychik RP.; 1997 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19614

•

Common Elements in Interleukin 4 and Insulin Signaling Pathways in FactorDependent Hematopoietic Cells. by Wang L, Keegan AD, Li W, Lienhard GE, Pacini S, Gutkind JS, Myers MG Jr, Sun X, White MF, Aaronson SA, Paul WE, Pierce JH.; 1993 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46440

•

Contraction Stimulates Translocation of Glucose Transporter GLUT4 in Skeletal Muscle Through a Mechanism Distinct from that of Insulin. by Lund S, Holman GD, Schmitz O, Pedersen O.; 1995 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41592

•

Correlation of [alpha]-Fetoprotein Expression in Normal Hepatocytes during Development with Tyrosine Phosphorylation and Insulin Receptor Expression. by Khamzina L, Borgeat P.; 1998 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25332

•

Cross Talk of pp125FAK and pp59Lyn Non-Receptor Tyrosine Kinases to InsulinMimetic Signaling in Adipocytes. by Muller G, Wied S, Frick W.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85892

•

Cross-Talk between the Insulin and Angiotensin Signaling Systems. by Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38019

•

Crystal structure of desheptapeptide(B24 --B30)insulin at 1.6 A resolution: Implications for receptor binding. by Bao SJ, Xie DL, Zhang JP, Chang WR, Liang DC.; 1997 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20307

•

Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins. by Tobe K, Sabe H, Yamamoto T, Yamauchi T, Asai S, Kaburagi Y, Tamemoto H, Ueki K, Kimura H, Akanuma Y, Yazaki Y, Hanafusa H, Kadowaki T.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231477

•

DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. by Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27038

86

Insulin

•

Decreased insulin binding to mononuclear leucocytes and erythrocytes from dogs by McGrowder D, after S-Nitroso-N-Acetypenicillamine administration. Ragoobirsingh D, Dasgupta T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65510

•

Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. by Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki JI, Seino S.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27906

•

Defective insulin secretion in pancreatic [beta] cells lacking type 1 IGF receptor. by Xuan S, Kitamura T, Nakae J, Politi K, Kido Y, Fisher PE, Morroni M, Cinti S, White MF, Herrera PL, Accili D, Efstratiadis A.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151144

•

Defects in inositol 1,4,5-trisphosphate receptor expression, Ca2 + signaling, and insulin secretion in the anx7( + /[minus sign]) knockout mouse. by Srivastava M, Atwater I, Glasman M, Leighton X, Goping G, Caohuy H, Miller G, Pichel J, Westphal H, Mears D, Rojas E, Pollard HB.; 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24142

•

Dephosphorylation of [beta]2-syntrophin and Ca2 + /[micro]-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion. by Ort T, Voronov S, Guo J, Zawalich K, Froehner SC, Zawalich W, Solimena M.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149140

•

Developmental regulation and the role of insulin and insulin receptor in metanephrogenesis. by Liu ZZ, Kumar A, Ota K, Wallner EI, Kanwar YS.; 1997 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21231

•

Differential Expression of the Two Nonallelic Proinsulin Genes in the Developing Mouse Embryo. by Deltour L, Leduque P, Blume N, Madsen O, Dubois P, Jami J, Bucchini D.; 1993 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45696

•

Differential Regulation of Secretory Compartments Containing the Insulinresponsive Glucose Transporter 4 in 3T3-L1 Adipocytes. by Millar CA, Shewan A, Hickson GR, James DE, Gould GW.; 1999 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25660

•

Direct Stimulation of Immediate-Early Genes by Intranuclear Insulin in TrypsinTreated H35 Hepatoma Cells. by Lin YJ, Harada S, Loten EG, Smith RM, Jarett L.; 1992 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50198

•

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. by Martinez NR, Augstein P, Moustakas AK, Papadopoulos GK, Gregori S, Adorini L, Jackson DC, Harrison LC.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154446

•

Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. by Chutkow WA, Samuel V, Hansen PA, Pu J, Valdivia CR, Makielski JC, Burant CF.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58803

Studies

87

•

Dissociation Between Changes in Cytoplasmic Free Ca2+ Concentration and Insulin Secretion as Evidenced from Measurements in Mouse Single Pancreatic Islets. by Zaitsev SV, Efendic S, Arkhammar P, Bertorello AM, Berggren P.; 1995 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40872

•

Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. by Weng W, Breslow JL.; 1996 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26214

•

Eighty years after insulin: parallels with modern islet transplantation. by Shapiro J.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137363

•

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. by Vosseller K, Wells L, Lane MD, Hart GW.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122766

•

Engineering of Glucose-Stimulated Insulin Secretion and Biosynthesis in Non-Islet Cells. by Hughes SD, Johnson JH, Quaade C, Newgard CB.; 1992 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48304

•

Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. by Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, Ribel U, Watanabe T, Drucker DJ, Wagtmann N.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18768

•

Evidence for a circulating islet cell growth factor in insulin-resistant states. by Flier SN, Kulkarni RN, Kahn CR.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34693

•

Evidence for an Insulin Receptor Substrate 1 Independent Insulin Signaling Pathway that Mediates Insulin-Responsive Glucose Transporter (GLUT4) Translocation. by Morris AJ, Martin SS, Haruta T, Nelson JG, Vollenweider P, Gustafson TA, Mueckler M, Rose DW, Olefsky JM.; 1996 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38683

•

Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. by Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr.; 1998 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22753

•

Evolution of the Insulin Superfamily: Cloning of a Hybrid Insulin/Insulin- Like Growth Factor cDNA from Amphioxus. by Chan SJ, Cao Q, Steiner DF.; 1990 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55156

•

Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: Differential effects on insulin-receptor substrates 1 and 2. by Chibalin AV, Yu M, Ryder JW, Song XM, Galuska D, Krook A, Wallberg-Henriksson H, Zierath JR.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26612

88

Insulin

•

Expression of an Insulin-Responsive Glucose Transporter (GLUT4) Minigene in Transgenic Mice: Effect of Exercise and Role in Glucose Homeostasis. by Ikemoto S, Thompson KS, Itakura H, Lane MD, Ezaki O.; 1995 Jan 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42721

•

Expression of multiple insulin and insulin-like growth factor receptor genes in salmon gill cartilage. by Chan SJ, Plisetskaya EM, Urbinati E, Jin Y, Steiner DF.; 1997 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24992

•

Expression of Yeast Hexokinase in Pancreatic [beta] Cells of Transgenic Mice Reduces Blood Glucose, Enhances Insulin Secretion, and Decreases Diabetes. by Epstein PN, Boschero AC, Atwater I, Cai X, Overbeek PA.; 1992 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50693

•

G Alpha-q/11 Protein Plays a Key Role in Insulin-Induced Glucose Transport in 3T3L1 Adipocytes. by Imamura T, Vollenweider P, Egawa K, Clodi M, Ishibashi K, Nakashima N, Ugi S, Adams JW, Brown JH, Olefsky JM.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84673

•

Gene Therapy for Diabetes Mellitus in Rats by Hepatic Expression of Insulin. by Kolodka TM, Finegold M, Moss L, Woo SL.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42152

•

Glucagon-like peptide 1 (1 --37) converts intestinal epithelial cells into insulinproducing cells. by Suzuki A, Nakauchi H, Taniguchi H.; 2003 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154293

•

Glucose Modulates the Binding of an Islet-Specific Factor to a Conserved Sequence Within the Rat I and the Human Insulin Promoters. by Melloul D, Ben-Neriah Y, Cerasi E.; 1993 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46406

•

Glucose Stimulation of Insulin Release in the Absence of Extracellular Ca2+ and in the Absence of any Increase in Intracellular Ca2+ in Rat Pancreatic Islets. by Komatsu M, Schermerhorn T, Aizawa T, Sharp GW.; 1995 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40685

•

GLUT4 Facilitates Insulin Stimulation and cAMP-Mediated Inhibition of Glucose Transport. by Lawrence JC Jr, Piper RC, Robinson LJ, James DE.; 1992 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48894

•

GLUT4 Retention in Adipocytes Requires Two Intracellular Insulin-regulated Transport Steps. by Zeigerer A, Lampson MA, Karylowski O, Sabatini DD, Adesnik M, Ren M, McGraw TE.; 2002 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117324

Studies

89

•

GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor --stimulated muscle glucose utilization. by Burcelin R, Crivelli V, Perrin C, Costa AD, Mu J, Kahn BB, Birnbaum MJ, Kahn CR, Vollenweider P, Thorens B.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155044

•

GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. by Carayannopoulos MO, Chi MM, Cui Y, Pingsterhaus JM, McKnight RA, Mueckler M, Devaskar SU, Moley KH.; 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16542

•

Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. by Pickup J, Mattock M, Kerry S.; 2002 Mar 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99054

•

Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBP[alpha] Kinase. by Ross SE, Erickson RL, Hemati N, MacDougald OA.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84944

•

gp160, a Tissue-Specific Marker for Insulin-Activated Glucose Transport. by Kandror KV, Pilch PF.; 1994 Aug 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44536

•

Grb10, a Positive, Stimulatory Signaling Adapter in Platelet-Derived Growth Factor BB-, Insulin-Like Growth Factor I-, and Insulin-Mediated Mitogenesis. by Wang J, Dai H, Yousaf N, Moussaif M, Deng Y, Boufelliga A, Swamy OR, Leone ME, Riedel H.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84567

•

Grb-IR: A SH2-Domain-Containing Protein that Binds to the Insulin Receptor and Inhibits Its Function. by Liu F, Roth RA.; 1995 Oct 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40781

•

Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. by Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138572

•

Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes. by O'Brien RM, Noisin EL, Suwanichkul A, Yamasaki T, Lucas PC, Wang JC, Powell DR, Granner DK.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230399

•

Hepatocyte Nuclear Factor 1[alpha] is Expressed in a Hamster Insulinoma Line and Transactivates the Rat Insulin I Gene. by Emens LA, Landers DW, Moss LG.; 1992 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49697

90

Insulin

•

Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription. by Streeper RS, Eaton EM, Ebert DH, Chapman SC, Svitek CA, O'Brien RM.; 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21317

•

Homologous DNA sequences and cellular factors are implicated in the control of glucagon and insulin gene expression. by Cordier-Bussat M, Morel C, Philippe J.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230630

•

Hyperinsulinemia Induces a Reversible Impairment in Insulin Receptor Function Leading to Diabetes in the Sand Rat Model of Non-Insulin-Dependent Diabetes Mellitus. by Kanety H, Moshe S, Shafrir E, Lunenfeld B, Karasik A.; 1994 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43262

•

Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. by Miyake K, Ogawa W, Matsumoto M, Nakamura T, Sakaue H, Kasuga M.; 2002 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151813

•

Hyperinsulinism induced by targeted suppression of beta cell KATP channels. by Koster JC, Remedi MS, Flagg TP, Johnson JD, Markova KP, Marshall BA, Nichols CG.; 2002 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139257

•

Identification of [beta]-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. by Olbrot M, Rud J, Moss LG, Sharma A.; 2002 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124472

•

Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats. by Chen ZW, Ahren B, Ostenson CG, Cintra A, Bergman T, Moller C, Fuxe K, Mutt V, Jornvall H, Efendic S.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28401

•

Immunoelectron Microscopic Demonstration of Insulin-Stimulated Translocation of Glucose Transporters to the Plasma Membrane of Isolated Rat Adipocytes and Masking of the Carboxyl-Terminal Epitope of Intracellular GLUT4. by Smith RM, Charron MJ, Shah N, Lodish HF, Jarett L.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52195

•

Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. by Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, McGuire JG, Pitas RE, Eckel RH, Farese RV Jr.; 2002 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150948

•

Increased insulin sensitivity in mice lacking p85[beta] subunit of phosphoinositide 3kinase. by Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC.; 2002 Jan 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117575

Studies

91

•

Induction and acceleration of insulitis /diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. by Moriyama H, Wen L, Abiru N, Liu E, Yu L, Miao D, Gianani R, Wong FS, Eisenbarth GS.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122805

•

Induction of Insulin and Islet Amyloid Polypeptide Production in Pancreatic Islet Glucagonoma Cells by Insulin Promoter Factor 1. by Serup P, Jensen J, Andersen FG, Jorgensen MC, Blume N, Holst JJ, Madsen OD.; 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38587

•

Inhibition of Clathrin-Mediated Endocytosis Selectively Attenuates Specific Insulin Receptor Signal Transduction Pathways. by Ceresa BP, Kao AW, Santeler SR, Pessin JE.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108970

•

Inositol hexakisphosphate stimulates non-Ca2 +-mediated and primes Ca2 +mediated exocytosis of insulin by activation of protein kinase C. by Efanov AM, Zaitsev SV, Berggren PO.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20740

•

Insulin Action on GLUT4 Traffic Visualized in Single 3T3-L1 Adipocytes by Using Ultra-fast Microscopy. by Patki V, Buxton J, Chawla A, Lifshitz L, Fogarty K, Carrington W, Tuft R, Corvera S.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30573

•

Insulin Activates a 70-kDa S6 Kinase Through Serine/Threonine-Specific Phosphorylation of the Enzyme Polypeptide. by Price DJ, Gunsalus JR, Avruch J.; 1990 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54868

•

Insulin alters heterogeneous nuclear ribonucleoprotein K protein binding to DNA and RNA. by Ostrowski J, Kawata Y, Schullery DS, Denisenko ON, Higaki Y, Abrass CK, Bomsztyk K.; 2001 Jul 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55370

•

Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: A novel mechanism of growth hormone receptor regulation. by Leung KC, Waters MJ, Markus I, Baumbach WR, Ho KK.; 1997 Oct 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23473

•

Insulin and the critically ill. by Das UN.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137452

•

Insulin can regulate GLUT4 internalization by signaling to Rab5 and the motor protein dynein. by Huang J, Imamura T, Olefsky JM.; 2001 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60828

•

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the MuscleSpecific Protein Phosphatase PP1G/RGL. by Suzuki Y, Lanner C, Kim JH, Vilardo PG, Zhang H, Yang J, Cooper LD, Steele M, Kennedy A, Bock CB, Scrimgeour A, Lawrence JC Jr, DePaoli-Roach AA.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86899

92

Insulin

•

Insulin depletion leads to adipose-specific cell death in obese but not lean mice. by Loftus TM, Kuhajda FP, Lane MD.; 1998 Nov 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24345

•

Insulin Down-Regulates Expression of the Insulin-Responsive Glucose Transporter (GLUT4) Gene: Effects on Transcription and mRNA Turnover. by Flores-Riveros JR, McLenithan JC, Ezaki O, Lane MD.; 1993 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45693

•

Insulin Gene Transcription Is Mediated by Interactions between the p300 Coactivator and PDX-1, BETA2, and E47. by Qiu Y, Guo M, Huang S, Stein R.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139753

•

Insulin increases near-membrane but not global Ca2 + in isolated skeletal muscle. by Bruton JD, Katz A, Westerblad H.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15933

•

Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating [beta]-Arrestin-1. by Dalle S, Imamura T, Rose DW, Sears Worrall D, Ugi S, Hupfeld CJ, Olefsky JM.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134007

•

Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes. by Zhang J, Ou J, Bashmakov Y, Horton JD, Brown MS, Goldstein JL.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31125

•

Insulin promotes rapid delivery of N-methyl-d- aspartate receptors to the cell surface by exocytosis. by Skeberdis VA, Lan JY, Zheng X, Zukin RS, Bennett MV.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30692

•

Insulin Promotes the Biosynthesis and Secretion of Apolipoprotein B-48 by Altering Apolipoprotein B mRNA Edition. by Thorngate FE, Raghow R, Wilcox HG, Werner CS, Heimberg M, Elam MB.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44001

•

Insulin Receptor Isotype Expression Correlates with Risk of Non-Insulin- Dependent Diabetes. by Mosthaf L, Eriksson J, Haring H, Groop L, Widen E, Ullrich A.; 1993 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46149

•

Insulin Receptor Substrate 1 is Required for Insulin-Mediated Mitogenic Signal Transduction. by Rose DW, Saltiel AR, Majumdar M, Decker SJ, Olefsky JM.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43036

•

Insulin Receptor Substrate 1 Mediates Insulin and Insulin-Like Growth Factor IStimulated Maturation of Xenopus Oocytes. by Chuang L, Myers MG Jr, Seidner GA, Birnbaum MJ, White MF, Kahn CR.; 1993 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46677

Studies

93

•

Insulin receptor substrate 1 rescues insulin action in CHO cells expressing mutant insulin receptors that lack a juxtamembrane NPXY motif. by Chen D, Van Horn DJ, White MF, Backer JM.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230714

•

Insulin Recruits GLUT4 from Specialized VAMP2-carrying Vesicles as well as from the Dynamic Endosomal/Trans-Golgi Network in Rat Adipocytes. by Ramm G, Slot JW, James DE, Stoorvogel W.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15058

•

Insulin Regulation of the Glucagon Gene is Mediated by an Insulin- Responsive DNA Element. by Philippe J.; 1991 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52266

•

Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. by Goldfine AB, Bouche C, Parker RA, Kim C, Kerivan A, Soeldner JS, Martin BC, Warram JH, Kahn CR.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151408

•

Insulin secretion is regulated by the glucose-dependent production of islet [beta] cell macrophage migration inhibitory factor. by Waeber G, Calandra T, Roduit R, Haefliger JA, Bonny C, Thompson N, Thorens B, Temler E, Meinhardt A, Bacher M, Metz CN, Nicod P, Bucala R.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20802

•

Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. by Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL.; 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24120

•

Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. by Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, Zhang D, Cooksey RC, McClain DA, Litwin SE, Taegtmeyer H, Severson D, Kahn CR, Abel ED.; 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150890

•

Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. by Fisher SJ, Kahn CR.; 2003 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151923

•

Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. by Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, Sonenberg N, Yazaki Y, Kadowaki T.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231302

•

Insulin Stimulates the Biosynthesis of Chiro-Inositol-Containing Phospholipids in a Rat Fibroblast Line Expressing the Human Insulin Receptor. by Pak Y, Paule CR, Bao Y, Huang LC, Larner J.; 1993 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47222

94

Insulin

•

Insulin stimulation of a MEK-dependent but ERK-independent SOS protein kinase. by Holt KH, Kasson BG, Pessin JE.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231036

•

Insulin-Activated Protein Kinase C[beta] Bypasses Ras and Stimulates MitogenActivated Protein Kinase Activity and Cell Proliferation in Muscle Cells. by Formisano P, Oriente F, Fiory F, Caruso M, Miele C, Maitan MA, Andreozzi F, Vigliotta G, Condorelli G, Beguinot F.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86107

•

Insulin-degrading enzyme regulates the levels of insulin, amyloid [beta]-protein, and the [beta]-amyloid precursor protein intracellular domain in vivo. by Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153065

•

Insulin-Induced Activation of Glycerol-3-Phosphate Acyltransferase by a ChiroInositol-Containing Insulin Mediator is Defective in Adipocytes of Insulin-Resistant, Type II Diabetic, Goto-Kakizaki Rats. by Farese RV, Standaert ML, Yamada K, Huang LC, Zhang C, Cooper DR, Wang Z, Yang Y, Suzuki S, Toyota T, Larner J.; 1994 Nov 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45162

•

Insulin-Induced Phosphorylation and Activation of Cyclic Nucleotide Phosphodiesterase 3B by the Serine-Threonine Kinase Akt. by Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84592

•

Insulin-induced Stimulation of Na +,K +-ATPase Activity in Kidney Proximal Tubule Cells Depends on Phosphorylation of the [alpha]-Subunit at Tyr-10. by Feraille E, Carranza ML, Gonin S, Beguin P, Pedemonte C, Rousselot M, Caverzasio J, Geering K, Martin PY, Favre H.; 1999 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25522

•

Insulin-Induced Surface Redistribution Regulates Internalization of the Insulin Receptor and Requires its Autophosphorylation. by Carpentier J, Paccaud J, Gorden P, Rutter WJ, Orci L.; 1992 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48196

•

Insulin-Like Growth Factor I Shifts from Promoting Cell Division to Potentiating Maturation During Neuronal Differentiation. by Pahlman S, Meyerson G, Lindgren E, Schalling M, Johansson I.; 1991 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52853

•

Insulin-like growth factor II signaling through the insulin-like growth factor II /mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells. by Zhang Q, Tally M, Larsson O, Kennedy RT, Huang L, Hall K, Berggren PO.; 1997 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21032

•

Insulin-regulated Release from the Endosomal Recycling Compartment Is Regulated by Budding of Specialized Vesicles. by Lampson MA, Schmoranzer J, Zeigerer A, Simon SM, McGraw TE.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60270

Studies

95

•

Insulin-Responsive Compartments Containing GLUT4 in 3T3-L1 and CHO Cells: Regulation by Amino Acid Concentrations. by Bogan JS, McKee AE, Lodish HF.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87167

•

Insulin's effect on glucose production: direct or indirect? by Barrett EJ.; 2003 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151931

•

Insulin-Secreting Non-Islet Cells are Resistant to Autoimmune Destruction. by Lipes MA, Cooper EM, Skelly R, Rhodes CJ, Boschetti E, Weir GC, Davalli AM.; 1996 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38718

•

Insulin-stimulated disassociation of the SOS-Grb2 complex. by Waters SB, Yamauchi K, Pessin JE.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230510

•

Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. by Huffman TA, Mothe-Satney I, Lawrence JC Jr.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117427

•

Insulin-stimulated translocation of GLUT4 glucose transporters requires SNAREcomplex proteins. by Cheatham B, Volchuk A, Kahn CR, Wang L, Rhodes CJ, Klip A.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26375

•

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade. by Ramalingam TS, Chakrabarti A, Edidin M.; 1997 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25720

•

Intracellular pH in Adipocytes: Effects of Free Fatty Acid Diffusion across the Plasma Membrane, Lipolytic Agonists, and Insulin. by Civelek VN, Hamilton JA, Tornheim K, Kelly KL, Corkey BE.; 1996 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38350

•

Intrasteric Inhibition of ATP Binding Is Not Required To Prevent Unregulated Autophosphorylation or Signaling by the Insulin Receptor. by Frankel M, Ablooglu AJ, Leone JW, Rusinova E, Ross JB, Heinrikson RL, Kohanski RA.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87081

•

Introduction of Exogenous Growth Hormone Receptors Augments Growth HormoneResponsive Insulin Biosynthesis in Rat Insulinoma Cells. by Billestrup N, Moldrup A, Serup P, Mathews LS, Norstedt G, Nielsen JH.; 1990 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54713

•

IRS-4 Mediates Protein Kinase B Signaling during Insulin Stimulation without Promoting Antiapoptosis. by Uchida T, Myers MG Jr, White MF.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85068

•

Isolation and Amino Acid Sequences of Squirrel Monkey (Saimiri sciurea) Insulin and Glucagon. by Yu J, Eng J, Yalow RS.; 1990 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55254

96

Insulin

•

Kinetics of Insulin Aggregation in Aqueous Solutions upon Agitation in the Presence of Hydrophobic Surfaces. by Sluzky V, Tamada JA, Klibanov AM, Langer R.; 1991 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52720

•

Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. by Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR.; 2003 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161423

•

Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1[alpha] Knockout Mouse. by Lee YH, Sauer B, Gonzalez FJ.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110684

•

Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptindeficient ob /ob mice. by Seufert J, Kieffer TJ, Habener JF.; 1999 Jan 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15195

•

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis. by Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS.; 2003 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152262

•

Localization of Inositol Trisphosphate Receptor Subtype 3 to Insulin and Somatostatin Secretory Granules and Regulation of Expression in Islets and Insulinoma Cells. by Blondel O, Moody MM, Depaoli AM, Sharp AH, Ross CA, Swift H, Bell GI.; 1994 Aug 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44485

•

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. by Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, Okubo M, Murase T, Kamataki A, Yamamoto J, Magoori K, Takahashi S, Miyamoto Y, Oishi H, Nose M, Okazaki M, Usui S, Imaizumi K, Yanagisawa M, Sakai J, Yamamoto TT.; 2003 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140935

•

Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin. by Takano A, Usui I, Haruta T, Kawahara J, Uno T, Iwata M, Kobayashi M.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87231

•

Measurement and modeling of the transient difference between blood and subcutaneous glucose concentrations in the rat after injection of insulin. by Schmidtke DW, Freeland AC, Heller A, Bonnecaze RT.; 1998 Jan 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18205

•

Metabolic decompensation in pump users due to lispro insulin precipitation. by Wolpert HA, Faradji RN, Bonner-Weir S, Lipes MA.; 2002 May 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113278

•

Microinjection of a Protein-Tyrosine-Phosphatase Inhibits Insulin Action in Xenopus oocytes. by Cicirelli MF, Tonks NK, Diltz CD, Weiel JE, Fischer EH.; 1990 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54355

Studies

97

•

Mitochondrial Biogenesis and Remodeling during Adipogenesis and in Response to the Insulin Sensitizer Rosiglitazone. by Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, Czech M, Corvera S.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140688

•

Modulation of glucose responsiveness of insulinoma [beta]-cells by graded overexpression of glucokinase. by Wang H, Iynedjian PB.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20729

•

Modulation of the chaperone heat shock cognate 70 by embryonic (pro)insulin correlates with prevention of apoptosis. by de la Rosa EJ, Vega-Nunez E, Morales AV, Serna J, Rubio E, de Pablo F.; 1998 Aug 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21442

•

Molecular Cloning and Tissue Distribution of PHAS-I, an Intracellular Target for Insulin and Growth Factors. by Hu C, Pang S, Kong X, Velleca M, Lawrence JC Jr.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43655

•

Molecular cloning of an amphibian insulin receptor substrate 1-like cDNA and involvement of phosphatidylinositol 3-kinase in insulin-induced Xenopus oocyte maturation. by Liu XJ, Sorisky A, Zhu L, Pawson T.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230593

•

Molecular Mechanism of Insulin-Induced Degradation of Insulin Receptor Substrate 1. by Zhande R, Mitchell JJ, Wu J, Sun XJ.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134643

•

Molecular Structure of a Major Insulin/Mitogen-Activated 70-kDa S6 Protein Kinase. by Banerjee P, Ahmad MF, Grove JR, Kozlosky C, Price DJ, Avruch J.; 1990 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54994

•

Mouse Insulin-Responsive Glucose Transporter Gene: Characterization of the Gene and Trans-Activation by the CCAAT/Enhancer Binding Protein. by Kaestner KH, Christy RJ, Lane MD.; 1990 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53240

•

Muscle-specific PPAR[gamma]-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. by Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=171387

•

Naturally Processed Heterodimeric Disulfide-Linked Insulin Peptides Bind to Major Histocompatibility Class II Molecules on Thymic Epithelial Cells. by Forquet F, Hadzija M, Semple JW, Speck E, Delovitch TL.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43697

98

Insulin

•

Nck Associates with the SH2 Domain-Docking Protein IRS-1 in Insulin- Stimulated Cells. by Lee C, Li W, Nishimura R, Zhou M, Batzer AG, Myers MG Jr, White MF, Schlessinger J, Skolnik EY.; 1993 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48054

•

Nerve Growth Factor Induces Neuron-Like Differentiation of an Insulin-Secreting Pancreatic Beta Cell Line. by Polak M, Scharfmann R, Seilheimer B, Eisenbarth G, Dressler D, Verma IM, Potter H.; 1993 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46806

•

Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells. by Johnson JD, Misler S.; 2002 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137923

•

Nitric Oxide Mediates Cytokine-Induced Inhibition of Insulin Secretion by Human Islets of Langerhans. by Corbett JA, Sweetland MA, Wang JL, Lancaster JR Jr, McDaniel ML.; 1993 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45953

•

NMR Studies of Muscle Glycogen Synthesis in Insulin-Resistant Offspring of Parents with Non-Insulin-Dependent Diabetes Mellitus Immediately after GlycogenDepleting Exercise. by Price TB, Perseghin G, Duleba A, Chen W, Chase J, Rothman DL, Shulman RG, Shulman GI.; 1996 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39245

•

Obese Gene Expression: Reduction by Fasting and Stimulation by Insulin and Glucose in Lean Mice, and Persistent Elevation in Acquired (Diet-Induced) and Genetic (Yellow Agouti) Obesity. by Mizuno TM, Bergen H, Funabashi T, Kleopoulos SP, Zhong Y, Bauman WA, Mobbs CV.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39626

•

Opposite Effects of Insulin on Focal Adhesion Proteins in 3T3-L1 Adipocytes and in Cells Overexpressing the Insulin Receptor. by Wang Q, Bilan PJ, Klip A.; 1998 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25588

•

Optimizing Transmembrane Domain Helicity Accelerates Insulin Receptor Internalization and Lateral Mobility. by Goncalves E, Yamada K, Thatte HS, Backer JM, Golan DE, Kahn CR, Shoelson SE.; 1993 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46802

•

Osmotic Shock Inhibits Insulin Signaling by Maintaining Akt/Protein Kinase B in an Inactive Dephosphorylated State. by Chen D, Fucini RV, Olson AL, Hemmings BA, Pessin JE.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84266

•

Overexpression of [beta]2-Microglobulin in Transgenic Mouse Islet [beta] Cells Results in Defective Insulin Secretion. by Allison J, Malcolm L, Culvenor J, Bartholomeusz RK, Holmberg K, Miller JF.; 1991 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51170

Studies

99

•

Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. by Wang MY, Koyama K, Shimabukuro M, Mangelsdorf D, Newgard CB, Unger RH.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21741

•

Overexpression of SH2-Containing Inositol Phosphatase 2 Results in Negative Regulation of Insulin-Induced Metabolic Actions in 3T3-L1 Adipocytes via Its 5[prime prime or minute]-Phosphatase Catalytic Activity. by Wada T, Sasaoka T, Funaki M, Hori H, Murakami S, Ishiki M, Haruta T, Asano T, Ogawa W, Ishihara H, Kobayashi M.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86709

•

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. by Zabolotny JM, Kim YB, Peroni OD, Kim JK, Pani MA, Boss O, Klaman LD, Kamatkar S, Shulman GI, Kahn BB, Neel BG.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33185

•

p300 Mediates Transcriptional Stimulation by the Basic Helix-Loop-Helix Activators of the Insulin Gene. by Qiu Y, Sharma A, Stein R.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110675

•

Paradoxical Structure and Function in a Mutant Human Insulin Associated with Diabetes Mellitus. by Hua QX, Shoelson SE, Inouye K, Weiss MA.; 1993 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45707

•

Phenotypic alterations in insulin-deficient mutant mice. by Duvillie B, Cordonnier N, Deltour L, Dandoy-Dron F, Itier JM, Monthioux E, Jami J, Joshi RL, Bucchini D.; 1997 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24644

•

Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. by Eldar-Finkelman H, Krebs EG.; 1997 Sep 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23245

•

Phosphorylation State of the GLUT4 Isoform of the Glucose Transporter in Subfractions of the Rat Adipose Cell: Effects of Insulin, Adenosine, and Isoproterenol. by Nishimura H, Saltis J, Habberfield AD, Garty NB, Greenberg AS, Cushman SW, Londos C, Simpson IA.; 1991 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53163

•

PKC[lambda] in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. by Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K, Hayashi Y, Iguchi H, Matsuki Y, Hiramatsu R, Shimano H, Yamada N, Ohno S, Kasuga M, Noda T.; 2003 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193669

•

Platelet-Derived Growth Factor Triggers Translocation of the Insulin- Regulatable Glucose Transporter (Type 4) Predominantly Through Phosphatidylinositol 3-Kinase Binding Sites on the Receptor. by Kamohara S, Hayashi H, Todaka M, Kanai F, Ishii K, Imanaka T, Escobedo JA, Williams LT, Ebina Y.; 1995 Feb 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42640

100 Insulin

•

pp60Src Mediates Insulin-stimulated Sequestration of the [beta]2-Adrenergic Receptor: Insulin Stimulates pp60Src Phosphorylation and Activation. by Shumay E, Song X, Wang HY, Malbon CC.; 2002 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133605

•

Preserved Pancreatic [beta]-Cell Development and Function in Mice Lacking the Insulin Receptor-Related Receptor. by Kitamura T, Kido Y, Nef S, Merenmies J, Parada LF, Accili D.; 2001 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87283

•

Proinsulin Endoproteolysis Confers Enhanced Targeting of Processed Insulin to the Regulated Secretory Pathway. by Kuliawat R, Prabakaran D, Arvan P.; 2000 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14896

•

Proinsulin Processing by the Subtilisin-Related Proprotein Convertases Furin, PC2, and PC3. by Smeekens SP, Montag AG, Thomas G, Albiges-Rizo C, Carroll R, Benig M, Phillips LA, Martin S, Ohagi S, Gardner P, Swift HH, Steiner DF.; 1992 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50013

•

Protection of Nonobese Diabetic Mice from Diabetes by Intranasal or Subcutaneous Administration of Insulin Peptide B-(9-23). by Daniel D, Wegmann DR.; 1996 Jan 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40166

•

Protein kinase A takes center stage in ATP-dependent insulin secretion. by Blanpied TA, Augustine GJ.; 1999 Jan 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33544

•

Protein Kinase B/Akt Participates in GLUT4 Translocation by Insulin in L6 Myoblasts. by Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104360

•

Protein-Free Cell Culture on an Artificial Substrate with Covalently Immobilized Insulin. by Ito Y, Zheng J, Imanishi Y, Yonezawa K, Kasuga M.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39656

•

Protein-Tyrosine-Phosphatase SHPTP2 is a Required Positive Effector for Insulin Downstream Signaling. by Yaauchi K, Milarski KL, Saltiel AR, Pessin JE.; 1995 Jan 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42680

•

Proximity Measurements Between H-2 Antigens and the Insulin Receptor by Fluorescence Energy Transfer: Evidence That a Close Association Does Not Influence Insulin Binding. by Liegler T, Szollosi J, Hyun W, Goodenow RS.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52167

•

Pseudomonas pseudomallei-insulin interaction. by Currie B.; 1995 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=173524

•

PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. by Crosson SM, Khan A, Printen J, Pessin JE, Saltiel AR.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154451

•

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. by Zinker BA, Rondinone CM,

Studies

101

Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, Wilcox D, Jacobson P, Frost L, Kroeger PE, Reilly RM, Koterski S, Opgenorth TJ, Ulrich RG, Crosby S, Butler M, Murray SF, McKay RA, Bhanot S, Monia BP, Jirousek MR.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123261 •

Pur-1, a Zinc-Finger Protein that Binds to Purine-Rich Sequences, Transactivates an Insulin Promoter in Heterologous Cells. by Kennedy GC, Rutter WJ.; 1992 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50579

•

Purification of the [beta]-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells. by Marshak S, Totary H, Cerasi E, Melloul D.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26355

•

Ras Signaling in the Activation of Glucose Transport by Insulin. by Manchester J, Kong X, Lowry OH, Lawrence JC Jr.; 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43844

•

Recurrent generalised urticaria at insulin injection sites. by Sackey AH.; 2000 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27548

•

Redistribution of Glycolipid Raft Domain Components Induces Insulin-Mimetic Signaling in Rat Adipocytes. by Muller G, Jung C, Wied S, Welte S, Jordan H, Frick W.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87114

•

Reduced expression of the murine p85[alpha] subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. by Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR.; 2002 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150818

•

Reduction of Insulin Gene Transcription in HIT-T15 [beta] Cells Chronically Exposed to a Supraphysiologic Glucose Concentration is Associated with Loss of STF-1 Transcription Factor Expression. by Olson LK, Sharma A, Peshavaria M, Wright CV, Towle HC, Robertson RP, Stein R.; 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40937

•

Regulated Expression of an Insulin-Responsive Glucose Transporter (GLUT4) Minigene in 3T3-L1 Adipocytes and Transgenic Mice. by Ezaki O, Flores-Riveros JR, Kaestner KH, Gearhart J, Lane MD.; 1993 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46297

•

Regulation of insulin preRNA splicing by glucose. by Wang J, Shen L, Najafi H, Kolberg J, Matschinsky FM, Urdea M, German M.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20727

•

Regulation of Insulin Receptor Signaling by the Protein Tyrosine Phosphatase TCPTP. by Galic S, Klingler-Hoffmann M, Fodero-Tavoletti MT, Puryer MA, Meng TC, Tonks NK, Tiganis T.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149470

102 Insulin

•

Regulation of Insulin-Stimulated Glucose Transporter GLUT4 Translocation and Akt Kinase Activity by Ceramide. by Summers SA, Garza LA, Zhou H, Birnbaum MJ.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109130

•

Requirement for Activation of the Serine-Threonine Kinase Akt (Protein Kinase B) in Insulin Stimulation of Protein Synthesis but Not of Glucose Transport. by Kitamura T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, Matsumoto M, Maeda T, Konishi H, Kikkawa U, Kasuga M.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108953

•

Requirement of Atypical Protein Kinase C[lambda] for Insulin Stimulation of Glucose Uptake but Not for Akt Activation in 3T3-L1 Adipocytes. by Kotani K, Ogawa W, Matsumoto M, Kitamura T, Sakaue H, Hino Y, Miyake K, Sano W, Akimoto K, Ohno S, Kasuga M.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109280

•

Requirement of protein kinase C zeta for stimulation of protein synthesis by insulin. by Mendez R, Kollmorgen G, White MF, Rhoads RE.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232369

•

Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. by Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31136

•

Ribozyme-Mediated Attenuation of Pancreatic [beta]-Cell Glucokinase Expression in Transgenic Mice Results in Impaired Glucose-Induced Insulin Secretion. by Efrat S, Leiser M, Wu Y, Fusco-DeMane D, Emran OA, Surana M, Jetton TL, Magnuson MA, Weir G, Fleischer N.; 1994 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43307

•

Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. by Szanto I, Kahn CR.; 2000 Feb 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15805

•

Severe block in processing of proinsulin to insulin accompanied by elevation of des64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1 /3. by Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124908

•

Short-term regulation of insulin gene transcription by glucose. by Leibiger B, Moede T, Schwarz T, Brown GR, Kohler M, Leibiger IB, Berggren PO.; 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21334

•

Signal Transduction Convergence: Phorbol Esters and Insulin Inhibit Phosphoenolpyruvate Carboxykinase Gene Transcription Through the Same 10-BasePair Sequence. by O'Brien RM, Bonovich MT, Forest CD, Granner DK.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52130

Studies

103

•

SIP/SHIP inhibits Xenopus oocyte maturation induced by insulin and phosphatidylinositol 3-kinase. by Deuter-Reinhard M, Apell G, Pot D, Klippel A, Williams LT, Kavanaugh WM.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232105

•

SKIP Negatively Regulates Insulin-Induced GLUT4 Translocation and Membrane Ruffle Formation. by Ijuin T, Takenawa T.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141139

•

SOCS-6 Binds to Insulin Receptor Substrate 4, and Mice Lacking the SOCS-6 Gene Exhibit Mild Growth Retardation. by Krebs DL, Uren RT, Metcalf D, Rakar S, Zhang JG, Starr R, De Souza DP, Hanzinikolas K, Eyles J, Connolly LM, Simpson RJ, Nicola NA, Nicholson SE, Baca M, Hilton DJ, Alexander WS.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133908

•

Specific binding of proinsulin C-peptide to human cell membranes. by Rigler R, Pramanik A, Jonasson P, Kratz G, Jansson OT, Nygren PA, Stahl S, Ekberg K, Johansson BL, Uhlen S, Uhlen M, Jornvall H, Wahren J.; 1999 Nov 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23945

•

Stat5 is a physiological substrate of the insulin receptor. by Chen J, Sadowski HB, Kohanski RA, Wang LH.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20081

•

Stereospecific Dihaloalkane Binding in a pH-Sensitive Cavity in Cubic Insulin Crystals. by Gursky O, Fontano E, Bhyravbhatla B, Caspar DL.; 1994 Dec 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45443

•

Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. by Foretz M, Guichard C, Ferre P, Foufelle F.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23076

•

Stimulation of Glycogen Synthesis by Insulin in Human Erythroleukemia Cells Requires the Synthesis of Glycosyl-Phosphatidylinositol. by Lazar DF, Knez JJ, Medof ME, Cuatrecasas P, Saltiel AR.; 1994 Oct 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44877

•

Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. by Mendez R, Myers MG Jr, White MF, Rhoads RE.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231278

•

Strength of translation initiation signal sequence of mRNA as studied by quantification method: effect of nucleotide substitutions upon translation efficiency in rat preproinsulin mRNA. by Iida Y, Masuda T.; 1996 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146100

104 Insulin

•

Structural similarities among malaria toxins insulin second messengers, and bacterial endotoxin. by Caro HN, Sheikh NA, Taverne J, Playfair JH, Rademacher TW.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174245

•

Structure and Dynamics of Des-Pentapeptide-Insulin in Solution: The MoltenGlobule Hypothesis. by Hua Q, Kochoyan M, Weiss MA.; 1992 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48661

•

Substitution of the erbB-2 Oncoprotein Transmembrane Domain Activates the Insulin Receptor and Modulates the Action of Insulin and Insulin-Receptor Substrate 1. by Cheatham B, Shoelson SE, Yamada K, Goncalves E, Kahn CR.; 1993 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47132

•

Suppressed Intrinsic Catalytic Activity of GLUT1 Glucose Transporters in InsulinSensitive 3T3-L1 Adipocytes. by Harrison SA, Buxton JM, Czech MP.; 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52399

•

Suppression of Diabetes in Nonobese Diabetic Mice by Oral Administration of Porcine Insulin. by Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL.; 1991 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52906

•

Syntaxin 4, VAMP2, and/or VAMP3/cellubrevin are functional target membrane and vesicle SNAP receptors for insulin-stimulated GLUT4 translocation in adipocytes. by Olson AL, Knight JB, Pessin JE.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232091

•

Synthesis of an organoinsulin molecule that can be activated by antibody catalysis. by Worrall DS, McDunn JE, List B, Reichart D, Hevener A, Gustafson T, Barbas CF III, Lerner RA, Olefsky JM.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61072

•

T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. by Congia M, Patel S, Cope AP, De Virgiliis S, Sonderstrup G.; 1998 Mar 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19923

•

Thallium Counterion Distribution in Cubic Insulin Crystals Determined from Anomalous X-ray Diffraction Data. by Badger J, Li Y, Caspar DL.; 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43129

•

The AMP-activated protein kinase [alpha]2 catalytic subunit controls whole-body insulin sensitivity. by Viollet B, Andreelli F, Jorgensen SB, Perrin C, Geloen A, Flamez D, Mu J, Lenzner C, Baud O, Bennoun M, Gomas E, Nicolas G, Wojtaszewski JF, Kahn A, Carling D, Schuit FC, Birnbaum MJ, Richter EA, Burcelin R, Vaulont S.; 2003 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151837

Studies

105

•

The Diabetogenic Effects of Glucocorticoids are More Pronounced in Low-Than in High-Insulin Responders. by Wajngot A, Giacca A, Grill V, Vranic M, Efendic S.; 1992 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49432

•

The Differential Effects of pp120 (Ceacam 1) on the Mitogenic Action of Insulin and Insulin-Like Growth Factor 1 Are Regulated by the Nonconserved Tyrosine 1316 in the Insulin Receptor. by Soni P, Lakkis M, Poy MN, Fernstrom MA, Najjar SM.; 2000 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85733

•

The Drosophila insulin receptor activates multiple signaling pathways but requires insulin receptor substrate proteins for DNA synthesis. by Yenush L, Fernandez R, Myers MG Jr, Grammer TC, Sun XJ, Blenis J, Pierce JH, Schlessinger J, White MF.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231240

•

The Export of Major Histocompatibility Complex Class I Molecules from the Endoplasmic Reticulum of Rat Brown Adipose Cells Is Acutely Stimulated by Insulin. by Malide D, Yewdell JW, Bennink JR, Cushman SW.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30571

•

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic [beta] cell growth. by Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH III, Wright CV, White MF, Arden KC, Accili D.; 2002 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151657

•

The Formation of an Insulin-responsive Vesicular Cargo Compartment Is an Early Event in 3T3-L1 Adipocyte Differentiation. by El-Jack AK, Kandror KV, Pilch PF.; 1999 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25345

•

The Homeodomain of PDX-1 Mediates Multiple Protein-Protein Interactions in the Formation of a Transcriptional Activation Complex on the Insulin Promoter. by Ohneda K, Mirmira RG, Wang J, Johnson JD, German MS.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85207

•

The Inability of Phosphatidylinositol 3-Kinase Activation to Stimulate GLUT4 Translocation Indicates Additional Signaling Pathways are Required for InsulinStimulated Glucose Uptake. by Isakoff SJ, Taha C, Rose E, Marcusohn J, Klip A, Skolnik EY.; 1995 Oct 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40773

•

The Insulin Receptor with Phenylalanine Replacing Tyrosine-1146 Provides Evidence for Separate Signals Regulating Cellular Metabolism and Growth. by Wilden PA, Backer JM, Kahn CR, Cahill DA, Schroeder GJ, White MF.; 1990 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53899

106 Insulin

•

The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k. by von Manteuffel SR, Dennis PB, Pullen N, Gingras AC, Sonenberg N, Thomas G.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232392

•

The Ligand Specificities of the Insulin Receptor and the Insulin-Like Growth Factor I Receptor Reside in Different Regions of a Common Binding Site. by Kjeldsen T, Andersen AS, Wiberg FC, Rasmussen JS, Schaffer L, Balschmidt P, Moller KB, Moller NP.; 1991 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51668

•

The NeuroD1/BETA2 Sequences Essential for Insulin Gene Transcription Colocalize with Those Necessary for Neurogenesis and p300/CREB Binding Protein Binding. by Sharma A, Moore M, Marcora E, Lee JE, Qiu Y, Samaras S, Stein R.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=83927

•

The Pleckstrin Homology (PH) Domain-Interacting Protein Couples the Insulin Receptor Substrate 1 PH Domain to Insulin Signaling Pathways Leading to Mitogenesis and GLUT4 Translocation. by Farhang-Fallah J, Randhawa VK, Nimnual A, Klip A, Bar-Sagi D, Rozakis-Adcock M.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139823

•

The Pleckstrin Homology and Phosphotyrosine Binding Domains of Insulin Receptor Substrate 1 Mediate Inhibition of Apoptosis by Insulin. by Yenush L, Zanella C, Uchida T, Bernal D, White MF.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109262

•

The protofilament structure of insulin amyloid fibrils. by Jimenez JL, Nettleton EJ, Bouchard M, Robinson CV, Dobson CM, Saibil HR.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123117

•

The Rab27a/Granuphilin Complex Regulates the Exocytosis of Insulin-Containing Dense-Core Granules. by Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S, Takata K, Takeuchi T, Izumi T.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135591

•

The Ras Signaling Pathway Mimics Insulin Action on Glucose Transporter Translocation. by Kozma L, Baltensperger K, Klarlund J, Porras A, Santos E, Czech MP.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46531

•

The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. by Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154437

•

The Structure of a Complex of Hexameric Insulin and 4'-Hydroxyacetanilide. by Smith GD, Ciszak E.; 1994 Sep 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44704

Studies

107

•

The TC10-interacting protein CIP4 /2 is required for insulin-stimulated Glut4 translocation in 3T3L1 adipocytes. by Chang L, Adams RD, Saltiel AR.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130546

•

The Xenopus proglucagon gene encodes novel GLP-1-like peptides with insulinotropic properties. by Irwin DM, Satkunarajah M, Wen Y, Brubaker PL, Pederson RA, Wheeler MB.; 1997 Jul 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21529

•

Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. by Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34701

•

Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. by [No authors listed]; 2002 Oct 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128375

•

Transcriptional Down-Regulation by Insulin of the [beta]3-Adrenergic Receptor Expression in 3T3-F442A Adipocytes: A Mechanism for Repressing the cAMP Signaling Pathway. by Feve B, Elhadri K, Quignard-Boulange A, Pairault J.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44059

•

Transcriptional Regulation of the Human Insulin Gene is Dependent on the Homeodomain Protein STF1/IPF1 Acting Through the CT Boxes. by Petersen HV, Serup P, Leonard J, Michelsen BK, Madsen OD.; 1994 Oct 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45041

•

Transcriptional Stimulation of the [delta]1-Crystallin Gene by Insulin- Like Growth Factor I and Insulin Requires DNA Cis Elements in Chicken. by Alemany J, Borras T, de Pablo F.; 1990 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53898

•

Transdominant Inhibition of Tyrosine Kinase Activity in Mutant Insulin/ InsulinLike Growth Factor I Hybrid Receptors. by Treadway JL, Morrison BD, Soos MA, Siddle K, Olefsky J, Ullrich A, McClain DA, Pessin JE.; 1991 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50780

•

Transfection and overexpression of the calcium binding protein calbindin-D28k results in a stimulatory effect on insulin synthesis in a rat [beta] cell line (RIN 104638). by Reddy D, Pollock AS, Clark SA, Sooy K, Vasavada RC, Stewart AF, Honeyman T, Christakos S.; 1997 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20025

•

Transmembrane Signaling by an Insulin Receptor Lacking a Cytoplasmic [beta]Subunit Domain. by Sasaoka T, Takata Y, Kusari J, Anderson CM, Langlois WJ, Olefsky JM.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46514

108 Insulin

•

Tumor Necrosis Factor [alpha] Inhibits Signaling From the Insulin Receptor. by Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM.; 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43887

•

Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. by Nachum Z, Ben-Shlomo I, Weiner E, Shalev E.; 1999 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28269

•

Two Nonallelic Insulin Genes in Xenopus laevis are Expressed Differentially During Neurulation in Prepancreatic Embryos. by Shuldiner AR, de Pablo F, Moore CA, Roth J.; 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52365

•

Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. by Lew A, Rutter WJ, Kennedy GC.; 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18794

•

VAMP2, but Not VAMP3/Cellubrevin, Mediates Insulin-dependent Incorporation of GLUT4 into the Plasma Membrane of L6 Myoblasts. by Randhawa VK, Bilan PJ, Khayat ZA, Daneman N, Liu Z, Ramlal T, Volchuk A, Peng XR, Coppola T, Regazzi R, Trimble WS, Klip A.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14928

•

VAMP3 Null Mice Display Normal Constitutive, Insulin- and Exercise-Regulated Vesicle Trafficking. by Yang C, Mora S, Ryder JW, Coker KJ, Hansen P, Allen LA, Pessin JE.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86703

•

Water Structure in Cubic Insulin Crystals. by Badger J, Caspar DL.; 1991 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50864

•

YMXM motifs and signaling by an insulin receptor substrate 1 molecule without tyrosine phosphorylation sites. by Myers MG Jr, Zhang Y, Aldaz GA, Grammer T, Glasheen EM, Yenush L, Wang LM, Sun XJ, Blenis J, Pierce JH, White MF.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231411

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

Studies

109

sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with insulin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “insulin” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for insulin (hyperlinks lead to article summaries): •

A comparison of postprandial and preprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Author(s): Danne T, Aman J, Schober E, Deiss D, Jacobsen JL, Friberg HH, Jensen LH; ANA 1200 Study Group. Source: Diabetes Care. 2003 August; 26(8): 2359-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882862&dopt=Abstract

•

A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. Author(s): Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K, Forsberg M, Volkmann R, Carvalho E, Funahashi T, Matsuzawa Y, Wiklund O, Yang X, Taskinen MR, Smith U. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 August; 17(11): 1434-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890697&dopt=Abstract

•

A novel insulin analog with unique properties: LysB3,GluB29 insulin induces prominent activation of insulin receptor substrate 2, but marginal phosphorylation of insulin receptor substrate 1. Author(s): Rakatzi I, Ramrath S, Ledwig D, Dransfeld O, Bartels T, Seipke G, Eckel J. Source: Diabetes. 2003 September; 52(9): 2227-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941761&dopt=Abstract

•

A patient with primary biliary cirrhosis complicated with slowly progressive insulindependent diabetes mellitus. Author(s): Nakasone H, Kinjo K, Yamashiro M, Kamiyama T, Kamiyama S, Miyazato H, Matsushita T, Arakawa Y, Ohshiro T, Toma S, Chinen K, Yamashiro M, Miyagi M, Makishi T, Hokama A, Sakugawa H, Kinjo F, Saito A. Source: Intern Med. 2003 June; 42(6): 496-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857047&dopt=Abstract

•

A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Author(s): Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G. Source: Diabetes. 2003 July; 52(7): 1611-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829623&dopt=Abstract

110 Insulin

•

A radioligand-binding assay for detecting antibodies specific for proinsulin and insulin using 35S-proinsulin. Author(s): Valdez SN, Iacono RF, Villalba A, Cardoso Landaburu A, Ermacora MR, Poskus E. Source: Journal of Immunological Methods. 2003 August; 279(1-2): 173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12969558&dopt=Abstract

•

Absence of profound hyperinsulinism in polycystic ovary syndrome is associated with subtle elevations in the plasminogen activator inhibitor system. Author(s): Sills ES, Drews CD, Perloe M, Tucker MJ, Kaplan CR, Palermo GD. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 June; 17(3): 231-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857431&dopt=Abstract

•

Acculturation and psychosocial stress show differential relationships to insulin resistance (HOMA) and body fat distribution in two groups of blacks living in the US Virgin Islands. Author(s): Tull ES, Thurland A, LaPorte RE, Chambers EC. Source: Journal of the National Medical Association. 2003 July; 95(7): 560-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911254&dopt=Abstract

•

Action of mifepristone on the expression of insulin-like growth factor binding protein-1 mRNA and protein during the early luteal phase in the human oviduct. Author(s): Qiu X, Sun X, Christow A, Stabi B, Gemzell-Danielsson K. Source: Fertility and Sterility. 2003 September; 80 Suppl 2: 776-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14505753&dopt=Abstract

•

Activating point mutations in cyclin-dependent kinase 4 are not seen in sporadic pituitary adenomas, insulinomas or Leydig cell tumours. Author(s): Vax VV, Bibi R, Diaz-Cano S, Gueorguiev M, Kola B, Borboli N, Bressac-de Paillerets B, Walker GJ, Dedov II, Grossman AB, Korbonits M. Source: The Journal of Endocrinology. 2003 August; 178(2): 301-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904177&dopt=Abstract

•

Activation of alpha2-adrenergic receptors blunts epinephrine-induced lipolysis in subcutaneous adipose tissue during a hyperinsulinemic euglycemic clamp in men. Author(s): Stich V, Pelikanova T, Wohl P, Sengenes C, Zakaroff-Girard A, Lafontan M, Berlan M. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 September; 285(3): E599-607. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900381&dopt=Abstract

Studies

111

•

Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. Author(s): Beeson M, Sajan MP, Dizon M, Grebenev D, Gomez-Daspet J, Miura A, Kanoh Y, Powe J, Bandyopadhyay G, Standaert ML, Farese RV. Source: Diabetes. 2003 August; 52(8): 1926-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882907&dopt=Abstract

•

Acute in vivo elevation of insulin-like growth factor (IGF) binding protein-1 decreases plasma free IGF-I and muscle protein synthesis. Author(s): Lang CH, Vary TC, Frost RA. Source: Endocrinology. 2003 September; 144(9): 3922-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933666&dopt=Abstract

•

Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Author(s): Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Source: Diabetes. 2003 July; 52(7): 1779-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829646&dopt=Abstract

•

Adipose tissue as an endocrine organ: impact on insulin resistance. Author(s): Jazet IM, Pijl H, Meinders AE. Source: The Netherlands Journal of Medicine. 2003 June; 61(6): 194-212. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948164&dopt=Abstract

•

Adjusting mealtime insulin based on meal carbohydrate content improves glycemic control and quality of life. Author(s): Franz MJ. Source: Curr Diab Rep. 2003 October; 3(5): 395-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975029&dopt=Abstract

•

Age or waist as determinant of insulin action? Author(s): Bryhni B, Jenssen TG, Olafsen K, Eikrem JH. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 850-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870160&dopt=Abstract

•

Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. Author(s): Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4398-406. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970316&dopt=Abstract

112 Insulin

•

Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans. Author(s): Giordano R, Grottoli S, Brossa P, Pellegrino M, Destefanis S, Lanfranco F, Gianotti L, Ghigo E, Arvat E. Source: Clinical Endocrinology. 2003 September; 59(3): 314-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919154&dopt=Abstract

•

Alteration of the counterregulatory responses to insulin-induced hypoglycemia and of cognitive function after massive weight reduction in severely obese subjects. Author(s): Guldstrand M, Ahren B, Wredling R, Backman L, Lins PE, Adamson U. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 900-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870168&dopt=Abstract

•

An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Author(s): Maloney EK, McLaughlin JL, Dagdigian NE, Garrett LM, Connors KM, Zhou XM, Blattler WA, Chittenden T, Singh R. Source: Cancer Research. 2003 August 15; 63(16): 5073-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941837&dopt=Abstract

•

An investigation of fetal, postnatal and childhood growth with insulin-like growth factor I and binding protein 3 in adulthood. Author(s): Ben-Shlomo Y, Holly J, McCarthy A, Savage P, Davies D, Gunnell D, Davey Smith G. Source: Clinical Endocrinology. 2003 September; 59(3): 366-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919161&dopt=Abstract

•

Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP). Author(s): Lew RA, Mustafa T, Ye S, McDowall SG, Chai SY, Albiston AL. Source: Journal of Neurochemistry. 2003 July; 86(2): 344-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871575&dopt=Abstract

•

Assessment of insulin sensitivity based on a fasting blood sample in men with liver cirrhosis before and after liver transplantation. Author(s): Perseghin G, Caumo A, Mazzaferro V, Pulvirenti A, Piceni Sereni L, Romito R, Lattuada G, Coppa J, Costantino F, Regalia E, Luzi L. Source: Transplantation. 2003 August 27; 76(4): 697-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12973112&dopt=Abstract

Studies

113

•

Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam Study. Author(s): Rivadeneira F, Houwing-Duistermaat JJ, Vaessen N, Vergeer-Drop JM, Hofman A, Pols HA, Van Duijn CM, Uitterlinden AG. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3878-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915683&dopt=Abstract

•

Association between insulin-like growth factor I (IGF-I) polymorphisms, circulating IGF-I, and pre- and postnatal growth in two European small for gestational age populations. Author(s): Johnston LB, Dahlgren J, Leger J, Gelander L, Savage MO, Czernichow P, Wikland KA, Clark AJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4805-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557458&dopt=Abstract

•

Association of lipoprotein(a), insulin resistance, and reproductive hormones in a multiethnic cohort of pre- and perimenopausal women (The SWAN Study). Author(s): Sowers M, Crawford SL, Cauley JA, Stein E. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 533-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943872&dopt=Abstract

•

Association of muscle glycogen synthase polymorphism with insulin resistance in type 2 diabetic patients. Author(s): Motoyama K, Emoto M, Tahara H, Komatsu M, Shoji T, Inaba M, Nishizawa Y. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 895-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870167&dopt=Abstract

•

Associations between insulin resistance and thrombotic risk factors in high-risk South Asian subjects. Author(s): Kain K, Catto AJ, Grant PJ. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 651-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873293&dopt=Abstract

•

ATP-sensitive potassium channels induced in liver cells after transfection with insulin cDNA and the GLUT 2 transporter regulate glucose-stimulated insulin secretion. Author(s): Liu GJ, Simpson AM, Swan MA, Tao C, Tuch BE, Crawford RM, Jovanovic A, Martin DK. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 September; 17(12): 1682-4. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958175&dopt=Abstract

114 Insulin

•

Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients. Author(s): Alvarsson M, Sundkvist G, Lager I, Henricsson M, Berntorp K, FernqvistForbes E, Steen L, Westermark G, Westermark P, Orn T, Grill V. Source: Diabetes Care. 2003 August; 26(8): 2231-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882841&dopt=Abstract

•

Benefits of combination therapy of insulin and oral hypoglycemic agents. Author(s): Garber AJ. Source: Archives of Internal Medicine. 2003 August 11-25; 163(15): 1781-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912710&dopt=Abstract

•

Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast. Author(s): Sawyer EJ, Hanby AM, Poulsom R, Jeffery R, Gillett CE, Ellis IO, Ellis P, Tomlinson IP. Source: The Journal of Pathology. 2003 August; 200(5): 627-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898599&dopt=Abstract

•

Beta-cell capacity and insulin sensitivity in prepubertal children born small for gestational age: influence of body size during childhood. Author(s): Veening MA, van Weissenbruch MM, Heine RJ, Delemarre-van de Waal HA. Source: Diabetes. 2003 July; 52(7): 1756-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829643&dopt=Abstract

•

Bilateral internal thoracic artery grafting in insulin-treated diabetics: should it be avoided? Author(s): Lev-Ran O, Mohr R, Amir K, Matsa M, Nehser N, Locker C, Uretzky G. Source: The Annals of Thoracic Surgery. 2003 June; 75(6): 1872-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822630&dopt=Abstract

•

Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate. Author(s): Martinetti A, Zilembo N, Ferrari L, Massimini G, Polli A, La Torre I, Giovanazzi R, Pozzi P, Bidoli P, De Candis D, Seregni E, Bombardieri E, Bajetta E. Source: Anticancer Res. 2003 July-August; 23(4): 3485-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926095&dopt=Abstract

•

Brain repair and neuroprotection by serum insulin-like growth factor I. Author(s): Carro E, Trejo JL, Nunez A, Torres-Aleman I. Source: Molecular Neurobiology. 2003 April; 27(2): 153-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777685&dopt=Abstract

Studies

115

•

Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors. Author(s): Kiyama S, Morrison K, Zellweger T, Akbari M, Cox M, Yu D, Miyake H, Gleave ME. Source: Cancer Research. 2003 July 1; 63(13): 3575-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839944&dopt=Abstract

•

Central pro-opiomelanocortin gene delivery results in hypophagia, reduced visceral adiposity, and improved insulin sensitivity in genetically obese Zucker rats. Author(s): Li G, Mobbs CV, Scarpace PJ. Source: Diabetes. 2003 August; 52(8): 1951-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882910&dopt=Abstract

•

Chromium supplements, glucose, and insulin responses. Author(s): Juturu V, Komorowski JR. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 190; Author Reply 192-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816790&dopt=Abstract

•

Circulating adhesion molecules and carotid artery structural changes in patients with noninsulin-dependent diabetes mellitus. Author(s): Rizzoni D, Muiesan ML, Porteri E, Castellano M, Salvetti M, Monteduro C, De Ciuceis C, Boari G, Valentini U, Cimino A, Sleiman I, Agabiti-Rosei E. Source: Journal of Human Hypertension. 2003 July; 17(7): 463-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821953&dopt=Abstract

•

Circulating levels of insulin-like growth factor I, its binding proteins -1,-2, -3, Cpeptide and risk of postmenopausal breast cancer. Author(s): Keinan-Boker L, Bueno De Mesquita HB, Kaaks R, Van Gils CH, Van Noord PA, Rinaldi S, Riboli E, Seidell JC, Grobbee DE, Peeters PH. Source: International Journal of Cancer. Journal International Du Cancer. 2003 August 10; 106(1): 90-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794762&dopt=Abstract

•

Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. Author(s): Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4848-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557464&dopt=Abstract

116 Insulin

•

Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor. Author(s): Thornton PS, MacMullen C, Ganguly A, Ruchelli E, Steinkrauss L, Crane A, Aguilar-Bryan L, Stanley CA. Source: Diabetes. 2003 September; 52(9): 2403-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941782&dopt=Abstract

•

Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. Author(s): Grassi G, Seravalle G, Dell'Oro R, Trevano FQ, Bombelli M, Scopelliti F, Facchini A, Mancia G; CROSS Study. Source: Journal of Hypertension. 2003 September; 21(9): 1761-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923410&dopt=Abstract

•

Comparison among different insulin sensitivity indices in obese patients. Author(s): Mannucci E, Bardini G, Rotella F, Rotella CM. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 June; 20(6): 462-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12786680&dopt=Abstract

•

Comparison between insulin tolerance test, growth hormone (GH)-releasing hormone (GHRH), GHRH plus acipimox and GHRH plus GH-releasing peptide-6 for the diagnosis of adult GH deficiency in normal subjects, obese and hypopituitary patients. Author(s): Cordido F, Alvarez-Castro P, Isidro ML, Casanueva FF, Dieguez C. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 August; 149(2): 117-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887288&dopt=Abstract

•

Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Author(s): Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, Lilos P, Dickerman Z, Phillip M. Source: Pediatrics. 2003 September; 112(3 Pt 1): 559-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12949284&dopt=Abstract

•

Comparison of shelf-life estimates for a human insulin pharmaceutical preparation using the matrix and full-testing approaches. Author(s): Oliva A, Farina J, Llabres M. Source: Drug Development and Industrial Pharmacy. 2003 May; 29(5): 513-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779281&dopt=Abstract

Studies

117

•

Comparison of the effects of dried peas with those of potatoes in mixed meals on postprandial glucose and insulin concentrations in patients with type 2 diabetes. Author(s): Schafer G, Schenk U, Ritzel U, Ramadori G, Leonhardt U. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 99-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816777&dopt=Abstract

•

Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man. Author(s): Courtney CH, Atkinson AB, Ennis CN, Sheridan B, Bell PM. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1050-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898472&dopt=Abstract

•

Comparison of various simple insulin sensitivity and beta-cell function indices in lean hyperandrogenemic and normoandrogenemic young hirsute women. Author(s): Altuntas Y, Bilir M, Ozturk B, Gundogdu S. Source: Fertility and Sterility. 2003 July; 80(1): 133-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849815&dopt=Abstract

•

Complex with a phage display-derived peptide provides insight into the function of insulin-like growth factor I. Author(s): Schaffer ML, Deshayes K, Nakamura G, Sidhu S, Skelton NJ. Source: Biochemistry. 2003 August 12; 42(31): 9324-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899619&dopt=Abstract

•

Congestive heart failure and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) system. Author(s): Dreifuss P. Source: The American Journal of Cardiology. 2003 July 15; 92(2): 245-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860243&dopt=Abstract

•

Conjugated linoleic acid downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells. Author(s): Kim EJ, Kang IJ, Cho HJ, Kim WK, Ha YL, Park JH. Source: The Journal of Nutrition. 2003 August; 133(8): 2675-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888657&dopt=Abstract

•

Continuous subcutaneous insulin infusion in patients with diabetes mellitus. Author(s): Schiel R. Source: Therap Apher Dial. 2003 April; 7(2): 232-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918949&dopt=Abstract

118 Insulin

•

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Author(s): Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 8; 100(14): 8466-71. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832613&dopt=Abstract

•

Coping styles and quality of life in patients with non-insulin-dependent diabetes mellitus. Author(s): Coelho R, Amorim I, Prata J. Source: Psychosomatics. 2003 July-August; 44(4): 312-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832597&dopt=Abstract

•

Coupling of oral human or porcine insulin to the B subunit of cholera toxin (CTB) overcomes critical antigenic differences for prevention of type I diabetes. Author(s): Petersen JS, Bregenholt S, Apostolopolous V, Homann D, Wolfe T, Hughes A, De Jongh K, Wang M, Dyrberg T, Von Herrath MG. Source: Clinical and Experimental Immunology. 2003 October; 134(1): 38-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974752&dopt=Abstract

•

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans. Author(s): Langenberger H, Schaller G, Pleiner J, Mittermayer F, Bayerle-Eder M, Wolzt M. Source: British Journal of Clinical Pharmacology. 2003 June; 55(6): 526-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814445&dopt=Abstract

•

CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues. Author(s): Ulaner GA, Yang Y, Hu JF, Li T, Vu TH, Hoffman AR. Source: Endocrinology. 2003 October; 144(10): 4420-6. Epub 2003 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960026&dopt=Abstract

•

Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Author(s): Roubenoff R, Parise H, Payette HA, Abad LW, D'Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Source: The American Journal of Medicine. 2003 October 15; 115(6): 429-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563498&dopt=Abstract

Studies

119

•

Decreased expression of the insulin-like growth factor 1 receptor by ribozyme cleavage. Author(s): Shaw LC, Afzal A, Lewin AS, Timmers AM, Spoerri PE, Grant MB. Source: Investigative Ophthalmology & Visual Science. 2003 September; 44(9): 4105-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939334&dopt=Abstract

•

Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. Author(s): Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 642-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873291&dopt=Abstract

•

Degradation, cyclic adenosine monophosphate production, insulin secretion, and glycemic effects of two novel N-terminal Ala2-substituted analogs of glucosedependent insulinotropic polypeptide with preserved biological activity in vivo. Author(s): Gault VA, O'Harte FP, Harriott P, Flatt PR. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 679-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800091&dopt=Abstract

•

Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. Author(s): Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, Miyamoto S, Nakano M, Ogawa H. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3190-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843164&dopt=Abstract

•

Diabetes and heart failure: is insulin therapy the answer? Author(s): Levy WC, Hirsch IB. Source: Journal of the American College of Cardiology. 2003 September 17; 42(6): 1051-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678929&dopt=Abstract

•

Diagnosis and treatment of heart failure in primary health care among elderly patients with non-insulin-dependent diabetes mellitus, with special reference to use of echocardiography. Author(s): Halling A, Berglund J. Source: Scandinavian Journal of Primary Health Care. 2003 June; 21(2): 96-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877372&dopt=Abstract

120 Insulin

•

Diagnosis of adrenal insufficiency: Evaluation of the corticotropin-releasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. Author(s): Schmidt IL, Lahner H, Mann K, Petersenn S. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4193-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970286&dopt=Abstract

•

Diazoxide attenuates glucose-induced defects in first-phase insulin release and pulsatile insulin secretion in human islets. Author(s): Song SH, Rhodes CJ, Veldhuis JD, Butler PC. Source: Endocrinology. 2003 August; 144(8): 3399-405. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865318&dopt=Abstract

•

Direct measurements of the permeability surface area for insulin and glucose in human skeletal muscle. Author(s): Gudbjornsdottir S, Sjostrand M, Strindberg L, Wahren J, Lonnroth P. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4559-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557422&dopt=Abstract

•

Does glucocorticoid dysregulation contribute to the link between cigarette smoking and insulin resistance? Author(s): Girod JP, Brotman DJ. Source: Journal of the American College of Cardiology. 2003 August 20; 42(4): 771; Author Reply 771-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12932618&dopt=Abstract

•

Does high blood glucose mean more insulin? Type 1 diabetes management in children and adolescents. Author(s): Yee KC, Edwards KN. Source: Aust Fam Physician. 2003 September; 32(9): 727-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14524211&dopt=Abstract

•

Driving while under the influence of insulin. Author(s): King A. Source: The British Journal of General Practice : the Journal of the Royal College of General Practitioners. 2003 February; 53(487): 149. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12817363&dopt=Abstract

Studies

121

•

Early postnatal undernutrition in preterm infants and reduced risk of insulin resistance. Author(s): Yeung MY, Smyth JP. Source: Lancet. 2003 June 28; 361(9376): 2248-9; Author Reply 2249. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842393&dopt=Abstract

•

Effect of a high-protein, energy-restricted diet on body composition, glycemic control, and lipid concentrations in overweight and obese hyperinsulinemic men and women. Author(s): Farnsworth E, Luscombe ND, Noakes M, Wittert G, Argyiou E, Clifton PM. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 31-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816768&dopt=Abstract

•

Effect of angiotensin-converting enzyme inhibition on endothelial function and insulin sensitivity in hypertensive patients. Author(s): Tezcan H, Yavuz D, Toprak A, Akpinar I, Koc M, Deyneli O, Akalin S. Source: J Renin Angiotensin Aldosterone Syst. 2003 June; 4(2): 119-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806595&dopt=Abstract

•

Effect of bovine colostrum on anaerobic exercise performance and plasma insulinlike growth factor I. Author(s): Buckley JD, Brinkworth GD, Abbott MJ. Source: Journal of Sports Sciences. 2003 July; 21(7): 577-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848392&dopt=Abstract

•

Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Author(s): Kivircik BB, Alptekin K, Caliskan S, Comlekci A, Oruk G, Tumuklu M, Kurklu K, Arkar H, Turk A, Caliskan M, Yesil S. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 August; 27(5): 795-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921912&dopt=Abstract

•

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Author(s): Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 24; 100(13): 7996-8001. Epub 2003 Jun 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808136&dopt=Abstract

122 Insulin

•

Effect of malnutrition during the first year of life on adult plasma insulin and glucose tolerance. Author(s): Gonzalez-Barranco J, Rios-Torres JM, Castillo-Martinez L, Lopez-Alvarenga JC, Aguilar-Salinas CA, Bouchard C, Depres JP, Tremblay A. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1005-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898465&dopt=Abstract

•

Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Author(s): Courtney CH, McCance DR, Atkinson AB, Bassett J, Ennis CN, Sheridan B, Bell PM. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1147-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506621&dopt=Abstract

•

Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with Type 1 diabetes. Author(s): Bott U, Ebrahim S, Hirschberger S, Skovlund SE. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 626-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873289&dopt=Abstract

•

Effect of training on muscle triacylglycerol and structural lipids: a relation to insulin sensitivity? Author(s): Helge JW, Dela F. Source: Diabetes. 2003 August; 52(8): 1881-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882901&dopt=Abstract

•

Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients. Author(s): Norrelund H, Djurhuus C, Jorgensen JO, Nielsen S, Nair KS, Schmitz O, Christiansen JS, Moller N. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E737-43. Epub 2003 June 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799313&dopt=Abstract

•

Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. Author(s): Broglio F, Gottero C, Benso A, Prodam F, Destefanis S, Gauna C, Maccario M, Deghenghi R, van der Lely AJ, Ghigo E. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4268-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970297&dopt=Abstract

Studies

123

•

Effects of glucose-insulin-potassium solution on myocardial salvage and left ventricular function after primary angioplasty. Author(s): Castro PF, Larrain G, Baeza R, Corbalan R, Nazzal C, Greig DP, Miranda FP, Perez O, Acevedo M, Marchant E, Olea E, Gonzalez R. Source: Critical Care Medicine. 2003 August; 31(8): 2152-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12973173&dopt=Abstract

•

Effects of insulin-like growth factor-I deficiency and replacement therapy on the hematopoietic system in patients with Laron syndrome (primary growth hormone insensitivity). Author(s): Sivan B, Lilos P, Laron Z. Source: J Pediatr Endocrinol Metab. 2003 April-May; 16(4): 509-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793602&dopt=Abstract

•

Effects of tamoxifen on insulin-like growth factors, IGF binding proteins and IGFBP3 proteolysis in breast cancer patients. Author(s): Gronbaek H, Tanos V, Meirow D, Peretz T, Raz I, Flyvbjerg A. Source: Anticancer Res. 2003 May-June; 23(3C): 2815-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926118&dopt=Abstract

•

Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression. Author(s): Bhasin S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003; 37 Suppl 2: S142-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942389&dopt=Abstract

•

Endothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic pre-menopausal women. Author(s): Yavuz D, Deyneli O, Akpinar I, Yildiz E, Gozu H, Sezgin O, Haklar G, Akalin S. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 September; 149(3): 187-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943520&dopt=Abstract

•

Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagon-like peptide 1 receptor. Author(s): Wu L, Nicholson W, Wu CY, Xu M, McGaha A, Shiota M, Powers AC. Source: Gene Therapy. 2003 September; 10(19): 1712-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923570&dopt=Abstract

124 Insulin

•

Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. Author(s): Goodpaster BH, Katsiaras A, Kelley DE. Source: Diabetes. 2003 September; 52(9): 2191-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941756&dopt=Abstract

•

Epidermal growth factor and insulin short-term increase hPepT1-mediated glycylsarcosine uptake in Caco-2 cells. Author(s): Nielsen CU, Amstrup J, Nielsen R, Steffansen B, Frokjaer S, Brodin B. Source: Acta Physiologica Scandinavica. 2003 June; 178(2): 139-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780388&dopt=Abstract

•

Estrogen and insulin crosstalk: breast cancer risk implications. Author(s): McCance KL, Jones RE. Source: The Nurse Practitioner. 2003 May; 28(5): 12-23; Quiz 24-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792265&dopt=Abstract

•

Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. Author(s): Morelli C, Garofalo C, Bartucci M, Surmacz E. Source: Oncogene. 2003 June 26; 22(26): 4007-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821935&dopt=Abstract

•

Evaluation of diagnostic accuracy of insulin-like growth factor (IGF)-I and IGFbinding protein-3 in growth hormone-deficient children and adults using ROC plot analysis. Author(s): Boquete HR, Sobrado PG, Fideleff HL, Sequera AM, Giaccio AV, Suarez MG, Ruibal GF, Miras M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4702-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557444&dopt=Abstract

•

Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Author(s): Ouban A, Muraca P, Yeatman T, Coppola D. Source: Human Pathology. 2003 August; 34(8): 803-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506643&dopt=Abstract

•

Expression of insulin-like growth factor I receptor and survival in patients with clear cell renal cell carcinoma. Author(s): Parker A, Cheville JC, Lohse C, Cerhan JR, Blute ML. Source: The Journal of Urology. 2003 August; 170(2 Pt 1): 420-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853790&dopt=Abstract

Studies

125

•

Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes. Author(s): Johanson EH, Jansson PA, Lonn L, Matsuzawa Y, Funahashi T, Taskinen MR, Smith U, Axelsen M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4232-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970292&dopt=Abstract

•

Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Author(s): Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E906-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959938&dopt=Abstract

•

Five weeks of insulin-like growth factor-I treatment does not alter glucose kinetics or insulin sensitivity during a hyperglycemic clamp in older women. Author(s): Braun B, Friedlander AL, Pollack M, Butterfield GE, Marcus R, Hoffman AR. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1182-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506625&dopt=Abstract

•

Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception. Author(s): Ibanez L, De Zegher F. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4720-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557446&dopt=Abstract

•

Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal muscle satellite cells. Author(s): Machida S, Spangenburg EE, Booth FW. Source: Journal of Cellular Physiology. 2003 September; 196(3): 523-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891709&dopt=Abstract

•

Free fatty acids, insulin resistance, and pregnancy. Author(s): Sivan E, Boden G. Source: Curr Diab Rep. 2003 August; 3(4): 319-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866995&dopt=Abstract

126 Insulin

•

Gene expression in human cells with mutant insulin receptors. Author(s): Melis R, Pruett PB, Wang Y, Longo N. Source: Biochemical and Biophysical Research Communications. 2003 August 8; 307(4): 1013-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878213&dopt=Abstract

•

Generation of anti-insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1/MAC25) monoclonal antibodies and immunoassay: quantification of IGFBP-rP1 in human serum and distribution in human fluids and tissues. Author(s): Lopez-Bermejo A, Khosravi J, Corless CL, Krishna RG, Diamandi A, Bodani U, Kofoed EM, Graham DL, Hwa V, Rosenfeld RG. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3401-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843194&dopt=Abstract

•

Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein. Author(s): Miyahara A, Okamura-Oho Y, Miyashita T, Hoshika A, Yamada M. Source: Journal of Human Genetics. 2003; 48(8): 410-4. Epub 2003 July 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884081&dopt=Abstract

•

Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Author(s): Fritsche A, Schweitzer MA, Haring HU; 4001 Study Group. Source: Annals of Internal Medicine. 2003 June 17; 138(12): 952-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809451&dopt=Abstract

•

Global haplotype diversity in the human insulin gene region. Author(s): Stead JD, Hurles ME, Jeffreys AJ. Source: Genome Research. 2003 September; 13(9): 2101-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952878&dopt=Abstract

•

Glucose and insulin responses following 16 months of exercise training in overweight adults: the Midwest Exercise Trial. Author(s): Potteiger JA, Jacobsen DJ, Donnelly JE, Hill JO; Midwest Exercise Trial. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1175-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506624&dopt=Abstract

Studies

127

•

Glucose metabolism and insulin resistance in women with polycystic ovary syndrome during therapy with oral contraceptives containing cyproterone acetate or desogestrel. Author(s): Cagnacci A, Paoletti AM, Renzi A, Orru M, Pilloni M, Melis GB, Volpe A. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3621-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915645&dopt=Abstract

•

Glucose-dependent insulinotropic polypeptide analogues and their therapeutic potential for the treatment of obesity-diabetes. Author(s): Gault VA, Flatt PR, O'Harte FP. Source: Biochemical and Biophysical Research Communications. 2003 August 22; 308(2): 207-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901855&dopt=Abstract

•

Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. Author(s): van der Horst IC, Zijlstra F, van't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ; Zwolle Infarct Study Group. Source: Journal of the American College of Cardiology. 2003 September 3; 42(5): 784-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957421&dopt=Abstract

•

Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome. Author(s): Ducluzeau PH, Cousin P, Malvoisin E, Bornet H, Vidal H, Laville M, Pugeat M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3626-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915646&dopt=Abstract

•

Glycemic control with different premixed insulin in Taiwanese people with type two diabetes mellitus. Author(s): Su CC, Chen HS, Lin HD. Source: J Chin Med Assoc. 2003 March; 66(3): 155-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779035&dopt=Abstract

•

Gonadotropin-releasing hormone secretion from hypothalamic neurons: stimulation by insulin and potentiation by leptin. Author(s): Burcelin R, Thorens B, Glauser M, Gaillard RC, Pralong FP. Source: Endocrinology. 2003 October; 144(10): 4484-91. Epub 2003 July 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960084&dopt=Abstract

128 Insulin

•

Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Author(s): Surmacz E. Source: Oncogene. 2003 September 29; 22(42): 6589-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14528284&dopt=Abstract

•

Hierarchy of the beta-cell signals controlling insulin secretion. Author(s): Henquin JC, Ravier MA, Nenquin M, Jonas JC, Gilon P. Source: European Journal of Clinical Investigation. 2003 September; 33(9): 742-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925032&dopt=Abstract

•

Higher insulin concentrations are required to suppress gluconeogenesis than glycogenolysis in nondiabetic humans. Author(s): Adkins A, Basu R, Persson M, Dicke B, Shah P, Vella A, Schwenk WF, Rizza R. Source: Diabetes. 2003 September; 52(9): 2213-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941759&dopt=Abstract

•

High-insulinogenic nutrition--an etiologic factor for obesity and the metabolic syndrome? Author(s): Kopp W. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 840-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870158&dopt=Abstract

•

Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, and oral glucose insulin sensitivity index in nonobese, nondiabetic subjects with high-normal blood pressure. Author(s): Kanauchi M, Yamano S, Kanauchi K, Saito Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3444-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843200&dopt=Abstract

•

Homocysteinemia is not changed by 3-day insulin-induced normoglycemia in type 2 diabetic subjects. Author(s): Beauvieux MC, Rigalleau V, Perlemoine C, Baillet L, Gin H. Source: Diabetes Care. 2003 August; 26(8): 2475-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882887&dopt=Abstract

•

Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels of soluble IL-6 receptor and higher insulin-like growth factor 1. Author(s): D'Elia HF, Mattsson LA, Ohlsson C, Nordborg E, Carlsten H. Source: Arthritis Research & Therapy. 2003; 5(4): R202-9. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823855&dopt=Abstract

Studies

129

•

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes. Author(s): Fuglsang J, Lauszus F, Fylvbjerg A, Ovesen P. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4355-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557493&dopt=Abstract

•

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes. Author(s): Fuglsang J, Lauszus F, Flyvbjerg A, Ovesen P. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4355-61. Corrected and Republished In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970310&dopt=Abstract

•

Hyperinsulinism in infancy: understanding the pathophysiology. Author(s): Hussain K, Aynsley-Green A. Source: The International Journal of Biochemistry & Cell Biology. 2003 September; 35(9): 1312-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798345&dopt=Abstract

•

Hypertriglyceridemia-induced acute pancreatitis--treatment with heparin and insulin. Author(s): Monga A, Arora A, Makkar RP, Gupta AK. Source: Indian J Gastroenterol. 2003 May-June; 22(3): 102-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839385&dopt=Abstract

•

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Author(s): Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, Nakai Y, Ishibashi S. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1274-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564678&dopt=Abstract

•

Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. Author(s): Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, D'Haens E, Kleijer WJ, Fery F, van der Zon GC. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4251-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970295&dopt=Abstract

130 Insulin

•

Impact of blood pressure and insulin on the relationship between body fat and left ventricular structure. Author(s): Karason K, Sjostrom L, Wallentin I, Peltonen M. Source: European Heart Journal. 2003 August; 24(16): 1500-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919774&dopt=Abstract

•

Impaired insulin response after oral but not intravenous glucose in heart- and livertransplant recipients. Author(s): Henchoz E, D'Alessio DA, Gillet M, Halkic N, Matzinger O, Goy JJ, Chiolero R, Tappy L, Schneiter P. Source: Transplantation. 2003 September 27; 76(6): 923-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14508355&dopt=Abstract

•

Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma. Author(s): Wiesner TD, Bluher M, Windgassen M, Paschke R. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3632-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915647&dopt=Abstract

•

Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion. Author(s): Festa A, Hanley AJ, Tracy RP, D'Agostino R Jr, Haffner SM. Source: Circulation. 2003 October 14; 108(15): 1822-30. Epub 2003 September 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517163&dopt=Abstract

•

Influence of rosiglitazone treatment on beta-cell function in type 2 diabetes: evidence of an increased ability of glucose to entrain high-frequency insulin pulsatility. Author(s): Juhl CB, Hollingdal M, Porksen N, Prange A, Lonnqvist F, Schmitz O. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3794-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915671&dopt=Abstract

•

Inhaled insulin in diabetes mellitus. Author(s): Royle P, Waugh N, McAuley L, McIntyre L, Thomas S. Source: Cochrane Database Syst Rev. 2003; (3): Cd003890. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917994&dopt=Abstract

•

Injection of the insulin receptor alpha subunit increases blood glucose levels in mice. Author(s): Kanezaki Y, Matsushima R, Obata T, Nakaya Y, Matsumoto T, Ebina Y. Source: Biochemical and Biophysical Research Communications. 2003 September 26; 309(3): 572-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963028&dopt=Abstract

Studies

131

•

Insulin action and distribution of tissue blood flow. Author(s): Bergman RN. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4556-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557421&dopt=Abstract

•

Insulin ameliorates exercise ventilatory efficiency and oxygen uptake in patients with heart failure-type 2 diabetes comorbidity. Author(s): Guazzi M, Tumminello G, Matturri M, Guazzi MD. Source: Journal of the American College of Cardiology. 2003 September 17; 42(6): 104450. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678928&dopt=Abstract

•

Insulin and oral hypoglycemic agents should not be used in combination in the treatment of type 2 diabetes. Author(s): Westphal SA, Palumbo PJ. Source: Archives of Internal Medicine. 2003 August 11-25; 163(15): 1783-5; Discussion 1785. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912711&dopt=Abstract

•

Insulin dose or glycemic control for the critically ill? Author(s): Bertolini G, Latronico N, Brazzi L, Radrizzani D. Source: Critical Care Medicine. 2003 October; 31(10): 2565-6; Author Reply 2566. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530775&dopt=Abstract

•

Insulin pump therapy for type 2 diabetes. Author(s): Kirk SE. Source: Curr Diab Rep. 2003 October; 3(5): 373-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975026&dopt=Abstract

•

Insulin resistance and beta-cell dysfunction in normoglycaemic European women with a history of gestational diabetes. Author(s): Kousta E, Lawrence NJ, Godsland IF, Penny A, Anyaoku V, Millauer BA, Cela E, Johnston DG, Robinson S, McCarthy MI. Source: Clinical Endocrinology. 2003 September; 59(3): 289-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919151&dopt=Abstract

•

Insulin resistance, hemostatic factors, and hormone interactions in pre- and perimenopausal women: SWAN. Author(s): Sowers M, Derby C, Jannausch ML, Torrens JI, Pasternak R. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4904-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557472&dopt=Abstract

132 Insulin

•

Insulin resistance, hypertension, and coronary heart disease. Author(s): Reaven G. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2003 July-August; 5(4): 269-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939567&dopt=Abstract

•

Insulin resistance, inflammation, and the prediabetic state. Author(s): Haffner SM. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 18J-26J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957323&dopt=Abstract

•

Insulin sensitivity and secretion are related to catch-up growth in small-forgestational-age infants at age 1 year: results from a prospective cohort. Author(s): Soto N, Bazaes RA, Pena V, Salazar T, Avila A, Iniguez G, Ong KK, Dunger DB, Mericq MV. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3645-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915649&dopt=Abstract

•

Insulin sensitivity, insulin secretion, and glucose tolerance versus intima-media thickness in nondiabetic postmenopausal women. Author(s): Larsson H, Berglund G, Ahren B. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4791-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557456&dopt=Abstract

•

Insulin storage and stability update. Author(s): Keller KJ. Source: S D J Med. 2003 August; 56(8): 303-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971076&dopt=Abstract

•

Insulin therapy for type 2 diabetes. Author(s): Sasali A, Leahy JL. Source: Curr Diab Rep. 2003 October; 3(5): 378-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975027&dopt=Abstract

•

Insulin/protein kinase B signalling pathway upregulates metastasis-related phenotypes and molecules in H7721 human hepatocarcinoma cell line. Author(s): Qi HL, Zhang Y, Ma J, Guo P, Zhang XY, Chen HL. Source: European Journal of Biochemistry / Febs. 2003 September; 270(18): 3795-805. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950263&dopt=Abstract

Studies

133

•

Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study. Author(s): Payette H, Roubenoff R, Jacques PF, Dinarello CA, Wilson PW, Abad LW, Harris T. Source: Journal of the American Geriatrics Society. 2003 September; 51(9): 1237-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919235&dopt=Abstract

•

Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitro. Author(s): Aberg ND, Blomstrand F, Aberg MA, Bjorklund U, Carlsson B, CarlssonSkwirut C, Bang P, Ronnback L, Eriksson PS. Source: Journal of Neuroscience Research. 2003 October 1; 74(1): 12-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130502&dopt=Abstract

•

Insulin-like growth factor-I: a traffic control device on the road to tissue recovery. Author(s): Elsasser TH. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2003 October; 285(4): R722-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959917&dopt=Abstract

•

Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, Dchiro-inositol) for polycystic ovary syndrome. Author(s): Lord JM, Flight IH, Norman RJ. Source: Cochrane Database Syst Rev. 2003; (3): Cd003053. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917943&dopt=Abstract

•

Intra-arterial calcium stimulation test for detection of insulinomas: detection rate, responses of pancreatic peptides, and its relationship to differentiation of tumor cells. Author(s): Won JG, Tseng HS, Yang AH, Tang KT, Jap TS, Kwok CF, Lee CH, Lin HD. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1320-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564685&dopt=Abstract

•

Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Author(s): Bruce CR, Carey AL, Hawley JA, Febbraio MA. Source: Diabetes. 2003 September; 52(9): 2338-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941774&dopt=Abstract

•

Intrauterine factors, adiposity, and hyperinsulinaemia. Author(s): Prentice AM. Source: Bmj (Clinical Research Ed.). 2003 October 18; 327(7420): 880-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563718&dopt=Abstract

134 Insulin

•

Introduction: New insight into understanding the relation of type 2 diabetes mellitus, insulin resistance, and cardiovascular disease. Author(s): Hsueh WA. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 1J-2J. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957320&dopt=Abstract

•

Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. Author(s): Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR. Source: The Journal of Clinical Investigation. 2003 June; 111(12): 1835-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813019&dopt=Abstract

•

Lean, nondiabetic Asian Indians have decreased insulin sensitivity and insulin clearance, and raised leptin compared to Caucasians and Chinese subjects. Author(s): Liew CF, Seah ES, Yeo KP, Lee KO, Wise SD. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 July; 27(7): 784-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821962&dopt=Abstract

•

Limitations to subcutaneous insulin administration in type 1 diabetes. Author(s): Chen JW, Christiansen JS, Lauritzen T. Source: Diabetes, Obesity & Metabolism. 2003 July; 5(4): 223-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795655&dopt=Abstract

•

Lipid profile, insulin secretion, and insulin sensitivity in psoriasis. Author(s): Reynoso-von Drateln C, Martinez-Abundis E, Balcazar-Munoz BR, BustosSaldana R, Gonzalez-Ortiz M. Source: Journal of the American Academy of Dermatology. 2003 June; 48(6): 882-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789179&dopt=Abstract

•

Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in beta-cell function. Author(s): Andersen O, Haugaard SB, Andersen UB, Friis-Moller N, Storgaard H, Volund A, Nielsen JO, Iversen J, Madsbad S. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1343-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564688&dopt=Abstract

Studies

135

•

Lispro insulin and metformin versus other combination in the diabetes mellitus type 2 management after secondary oral antidiabetic drug failure. Author(s): Kokic S, Bukovic D, Radman M, Capkun V, Gabric N, Lesko V, Karelovic D, Stanceric T. Source: Coll Antropol. 2003 June; 27(1): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974145&dopt=Abstract

•

Longitudinal analysis of serum insulin-like growth factor-I and insulin-like growth factor binding protein-1 in antiphospholipid syndrome and in healthy pregnancy. Author(s): Stone S, Langford K, Seed PT, Khamashta MA, Hunt BJ, Poston L. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 274-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861174&dopt=Abstract

•

Long-term follow-up of 114 patients with congenital hyperinsulinism. Author(s): Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 July; 149(1): 43-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824865&dopt=Abstract

•

Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease. Author(s): Boger RH, Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H. Source: Circulation. 2003 May 27; 107(20): E193; Author Reply E193. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777324&dopt=Abstract

•

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. Author(s): Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de Zegher F. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2600-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788862&dopt=Abstract

•

Low-fat diet: effect on anthropometrics, blood pressure, glucose, and insulin in older women. Author(s): Hall WD, Feng Z, George VA, Lewis CE, Oberman A, Huber M, Fouad M, Cutler JA; Women's Health Trial: Feasibility Study in Minority Populations. Source: Ethn Dis. 2003 Summer; 13(3): 337-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894958&dopt=Abstract

•

Management of diabetes mellitus and insulin resistance in patients with cardiovascular disease. Author(s): Fonseca VA. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 50J-60J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957327&dopt=Abstract

136 Insulin

•

Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Author(s): Girnita L, Girnita A, Larsson O. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 8; 100(14): 8247-52. Epub 2003 June 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821780&dopt=Abstract

•

Measurement of insulin-like growth factor-I during military operational stress via a filter paper blood spot assay. Author(s): Nindl BC, Kellogg MD, Khosravi MJ, Diamandi A, Alemany JA, Pietila DM, Young AJ, Montain SJ. Source: Diabetes Technology & Therapeutics. 2003; 5(3): 455-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828831&dopt=Abstract

•

Mechanism of insulin sensitization by BMOV (bis maltolato oxo vanadium); unliganded vanadium (VO4) as the active component. Author(s): Peters KG, Davis MG, Howard BW, Pokross M, Rastogi V, Diven C, Greis KD, Eby-Wilkens E, Maier M, Evdokimov A, Soper S, Genbauffe F. Source: Journal of Inorganic Biochemistry. 2003 August 1; 96(2-3): 321-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888267&dopt=Abstract

•

Mechanisms and strategies for insulin resistance in acquired immune deficiency syndrome. Author(s): Grinspoon S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003; 37 Suppl 2: S85-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942379&dopt=Abstract

•

Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance. Author(s): Basu R, Breda E, Oberg AL, Powell CC, Dalla Man C, Basu A, Vittone JL, Klee GG, Arora P, Jensen MD, Toffolo G, Cobelli C, Rizza RA. Source: Diabetes. 2003 July; 52(7): 1738-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829641&dopt=Abstract

•

Medical advances. For many diabetics, development of oral insulin--whether via an inhaler or a capsule--could mean the end of daily needlesticks and the beginning of a simpler treatment regimen. Author(s): Becker C. Source: Modern Healthcare. 2003 September 8; 33(36): 32-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520835&dopt=Abstract

Studies

137

•

Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Author(s): Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Source: Molecular and Cellular Biology. 2003 September; 23(17): 6049-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917329&dopt=Abstract

•

Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis. Author(s): Chalasani N, Deeg MA, Persohn S, Crabb DW. Source: The American Journal of Gastroenterology. 2003 August; 98(8): 1849-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907343&dopt=Abstract

•

Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. Author(s): Vgontzas AN, Bixler EO, Chrousos GP. Source: Journal of Internal Medicine. 2003 July; 254(1): 32-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823641&dopt=Abstract

•

Methods for quantifying insulin resistance in human immunodeficiency viruspositive patients. Author(s): Chu JW, Abbasi F, Beatty GW, Khalili M, Koch J, Rosen A, Schmidt JM, Stansell JD, Reaven GM. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 858-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870161&dopt=Abstract

•

Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression. Author(s): Dupont J, Dunn SE, Barrett JC, LeRoith D. Source: Recent Progress in Hormone Research. 2003; 58: 325-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795426&dopt=Abstract

•

Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. Author(s): Bergman RN, Zaccaro DJ, Watanabe RM, Haffner SM, Saad MF, Norris JM, Wagenknecht LE, Hokanson JE, Rotter JI, Rich SS. Source: Diabetes. 2003 August; 52(8): 2168-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882937&dopt=Abstract

138 Insulin

•

Modified quantitative insulin sensitivity check index is better correlated to hyperinsulinemic glucose clamp than other fasting-based index of insulin sensitivity in different insulin-resistant states. Author(s): Rabasa-Lhoret R, Bastard JP, Jan V, Ducluzeau PH, Andreelli F, Guebre F, Bruzeau J, Louche-Pellissier C, MaItrepierre C, Peyrat J, Chagne J, Vidal H, Laville M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4917-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557474&dopt=Abstract

•

Modulation of systemic insulin-like growth factor-1 and its binding proteins after major burn injuries. Author(s): Ghahary A. Source: Critical Care Medicine. 2003 June; 31(6): 1879-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794443&dopt=Abstract

•

Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Author(s): Vincent MA, Montagnani M, Quon MJ. Source: Curr Diab Rep. 2003 August; 3(4): 279-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866989&dopt=Abstract

•

Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. Author(s): Johnston AM, Pirola L, Van Obberghen E. Source: Febs Letters. 2003 July 3; 546(1): 32-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829233&dopt=Abstract

•

Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia. Author(s): Lombardo F, De Luca F, Rosano M, Sferlazzas C, Lucanto C, Arrigo T, Messina MF, Crisafulli G, Wasniewska M, Valenzise M, Cucinotta D. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 July; 149(1): 53-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824866&dopt=Abstract

•

Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses. Author(s): J Clin Endocrinol Metab. 2003 Oct;88(10):4355-61 Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4342-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557493

Studies

139

•

Neuroscience. Insulin insults may spur Alzheimer's disease. Author(s): Taubes G. Source: Science. 2003 July 4; 301(5629): 40-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843374&dopt=Abstract

•

New insulins and quality of life. Author(s): Iafusco D. Source: Acta Biomed Ateneo Parmense. 2003; 74 Suppl 1: 18-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12817796&dopt=Abstract

•

Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Author(s): Poynten AM, Gan SK, Kriketos AD, O'Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, Campbell LV. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 699-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800094&dopt=Abstract

•

Nonalcoholic steatohepatitis and insulin resistance: interface between gastroenterologists and endocrinologists. Author(s): Scheen AJ, Luyckx FH. Source: Acta Clin Belg. 2003 March-April; 58(2): 81-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12836490&dopt=Abstract

•

Novel concepts in insulin regulation of hepatic gluconeogenesis. Author(s): Barthel A, Schmoll D. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E685-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959935&dopt=Abstract

•

Novel insulins and strict glycemic control. Analogues approximate normal insulin secretory response. Author(s): White JR Jr, Campbell RK, Hirsch IB. Source: Postgraduate Medicine. 2003 June; 113(6): 30-6. Erratum In: Postgrad Med. 2003 September; 114(3): 7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838802&dopt=Abstract

•

Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables. Author(s): Tassone F, Lanfranco F, Gianotti L, Pivetti S, Navone F, Rossetto R, Grottoli S, Gai V, Ghigo E, Maccario M. Source: Clinical Endocrinology. 2003 September; 59(3): 374-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919162&dopt=Abstract

140 Insulin

•

Optimizing glycemic control with insulin glargine. Author(s): Williams JB. Source: Diabetes Technology & Therapeutics. 2003; 5(3): 471-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828834&dopt=Abstract

•

Optimizing insulin regimens in type 1 diabetes. How to help patients get control of their life. Author(s): Bohannon NJ. Source: Postgraduate Medicine. 2003 June; 113(6): 39-42, 45-8, 54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838803&dopt=Abstract

•

Ovariectomy leads to increased insulin resistance in human apolipoprotein B transgenic mice lacking brown adipose tissue. Author(s): Siri PW, Ginsberg HN. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 659-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800087&dopt=Abstract

•

Oxidative stress is associated with adiposity and insulin resistance in men. Author(s): Urakawa H, Katsuki A, Sumida Y, Gabazza EC, Murashima S, Morioka K, Maruyama N, Kitagawa N, Tanaka T, Hori Y, Nakatani K, Yano Y, Adachi Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4673-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557439&dopt=Abstract

•

Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells. Author(s): Cao X, Gao Z, Robert CE, Greene S, Xu G, Xu W, Bell E, Campbell D, Zhu Y, Young R, Trucco M, Markmann JF, Naji A, Wolf BA. Source: Diabetes. 2003 September; 52(9): 2296-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941769&dopt=Abstract

•

Partially folded intermediates in insulin fibrillation. Author(s): Ahmad A, Millett IS, Doniach S, Uversky VN, Fink AL. Source: Biochemistry. 2003 October 7; 42(39): 11404-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516191&dopt=Abstract

•

Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance. Author(s): Silha JV, Krsek M, Hana V, Marek J, Jezkova J, Weiss V, Murphy LJ. Source: Clinical Endocrinology. 2003 June; 58(6): 736-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780751&dopt=Abstract

Studies

141

•

PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. Author(s): Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K, Hayashi Y, Iguchi H, Matsuki Y, Hiramatsu R, Shimano H, Yamada N, Ohno S, Kasuga M, Noda T. Source: The Journal of Clinical Investigation. 2003 September; 112(6): 935-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975478&dopt=Abstract

•

Plasma insulin, IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in northern Sweden. Author(s): Palmqvist R, Stattin P, Rinaldi S, Biessy C, Stenling R, Riboli E, Hallmans G, Kaaks R. Source: International Journal of Cancer. Journal International Du Cancer. 2003 October 20; 107(1): 89-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925961&dopt=Abstract

•

Plasmalemmal fatty acid transport is regulated in heart and skeletal muscle by contraction, insulin and leptin, and in obesity and diabetes. Author(s): Bonen A, Benton CR, Campbell SE, Chabowski A, Clarke DC, Han XX, Glatz JF, Luiken JJ. Source: Acta Physiologica Scandinavica. 2003 August; 178(4): 347-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864739&dopt=Abstract

•

Plasminogen activator inhibitor-1 (PAI-1) activity post myocardial infarction: the role of acute phase reactants, insulin-like molecules and promoter (4G/5G) polymorphism in the PAI-1 gene. Author(s): Panahloo A, Mohamed-Ali V, Gray RP, Humphries SE, Yudkin JS. Source: Atherosclerosis. 2003 June; 168(2): 297-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801613&dopt=Abstract

•

Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. Author(s): Juhan-Vague I, Alessi MC, Mavri A, Morange PE. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 July; 1(7): 1575-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871293&dopt=Abstract

•

Platelet count is independently associated with insulin resistance in non-obese Japanese type 2 diabetic patients. Author(s): Taniguchi A, Fukushima M, Seino Y, Sakai M, Yoshii S, Nagasaka S, Yamauchi I, Okumura T, Nin K, Tokuyama K, Yamadori N, Ogura M, Kuroe A, Nakai Y. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1246-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564674&dopt=Abstract

142 Insulin

•

Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3-L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates. Author(s): Whiteman EL, Chen JJ, Birnbaum MJ. Source: Endocrinology. 2003 September; 144(9): 3811-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933652&dopt=Abstract

•

Polycystic ovarian syndrome and insulin resistance in white and Mexican American women. Author(s): Gokcel A, Bagis T, Zeyneloglu HB. Source: American Journal of Obstetrics and Gynecology. 2003 June; 188(6): 1661; Author Reply 1661-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12825010&dopt=Abstract

•

Polycystic ovaries: the role of insulin. Author(s): Ahmed AS. Source: J R Soc Health. 2003 June; 123(2): 78-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852188&dopt=Abstract

•

Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. Author(s): Bonafe M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3299304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843179&dopt=Abstract

•

Polymorphic variation at the -202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk. Author(s): Schernhammer ES, Hankinson SE, Hunter DJ, Blouin MJ, Pollak MN. Source: International Journal of Cancer. Journal International Du Cancer. 2003 October 20; 107(1): 60-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925957&dopt=Abstract

•

Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Author(s): Schut AF, Janssen JA, Deinum J, Vergeer JM, Hofman A, Lamberts SW, Oostra BA, Pols HA, Witteman JC, van Duijn CM. Source: Stroke; a Journal of Cerebral Circulation. 2003 July; 34(7): 1623-7. Epub 2003 June 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791939&dopt=Abstract

Studies

143

•

Poor glycaemic control caused by insulin induced lipohypertrophy. Author(s): Chowdhury TA, Escudier V. Source: Bmj (Clinical Research Ed.). 2003 August 16; 327(7411): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919996&dopt=Abstract

•

Possible angiogenic roles of insulin-like growth factor II and its receptors in uterine vascular adaptation to pregnancy. Author(s): Herr F, Liang OD, Herrero J, Lang U, Preissner KT, Han VK, Zygmunt M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4811-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557459&dopt=Abstract

•

Postprandial lipidemia is normal in non-obese type 2 diabetic patients with relatively preserved insulin secretion. Author(s): Wagner AM, Ordonez-Llanos J, Arcelus R, Bonet R, Jorba O, SanchezQuesada JL, Alonso E, Julve J, Perez A. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1038-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898470&dopt=Abstract

•

Potential roles of insulin and IGF-1 in Alzheimer's disease. Author(s): Gasparini L, Xu H. Source: Trends in Neurosciences. 2003 August; 26(8): 404-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900169&dopt=Abstract

•

PPAR agonists in the treatment of insulin resistance and associated arterial disease. Author(s): Camejo G. Source: Int J Clin Pract Suppl. 2003 March; (134): 36-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793596&dopt=Abstract

•

Proinsulin C-peptide and its C-terminal pentapeptide: degradation in human serum and Schiff base formation with subsequent CO2 incorporation. Author(s): Melles E, Bergman T, Alvelius G, Jonsson A, Ekberg K, Wahren J, Jornvall H. Source: Cellular and Molecular Life Sciences : Cmls. 2003 May; 60(5): 1019-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827290&dopt=Abstract

•

Prolonged corrected QT interval is associated with acute and chronic hyperinsulinemia in nondiabetic subjects. Author(s): Laitinen T, Vauhkonen I, Niskanen L, Hartikainen J, Uusitupa M, Laakso M. Source: Diabetes Care. 2003 August; 26(8): 2480-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882892&dopt=Abstract

144 Insulin

•

Prolonged treatment of human osteoarthritic chondrocytes with insulin-like growth factor-I stimulates proteoglycan synthesis but not proteoglycan matrix accumulation in alginate cultures. Author(s): Loeser RF, Todd MD, Seely BL. Source: The Journal of Rheumatology. 2003 July; 30(7): 1565-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858460&dopt=Abstract

•

Protein-tyrosine phosphatase activity in human adipocytes is strongly correlated with insulin-stimulated glucose uptake and is a target of insulin-induced oxidative inhibition. Author(s): Wu X, Hardy VE, Joseph JI, Jabbour S, Mahadev K, Zhu L, Goldstein BJ. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 705-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800095&dopt=Abstract

•

PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells. Author(s): Kang-Park S, Lee YI, Lee YI. Source: Febs Letters. 2003 June 19; 545(2-3): 203-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804776&dopt=Abstract

•

Pump up your knowledge of insulin pumps. Author(s): Fain JA. Source: Nursing. 2003 June; 33(6): 51-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799589&dopt=Abstract

•

Quantification of insulin-mediated glucose disposal in HIV-infected individuals: comparison of patients treated and untreated with protease inhibitors. Author(s): Beatty G, Khalili M, Abbasi F, Chu J, Reaven GM, Rosen A, Schmidt JM, Stansell J, Koch J. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 May 1; 33(1): 34-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792353&dopt=Abstract

•

Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients. Author(s): Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka T, Komatsu M, Tahara H, Shoji T, Okuno Y, Nishizawa Y. Source: Diabetes Care. 2003 August; 26(8): 2426-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882874&dopt=Abstract

Studies

145

•

Re: “Serum insulin and glucose levels and breast cancer incidence: the Atherosclerosis Risk in Communities Study”. Author(s): Muti P. Source: American Journal of Epidemiology. 2003 September 15; 158(6): 607; Author Reply 608. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12965886&dopt=Abstract

•

Re: Insulin resistance and prostate cancer risk. Author(s): Stattin P, Kaaks R. Source: Journal of the National Cancer Institute. 2003 July 16; 95(14): 1086-7; Author Reply 1087. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865455&dopt=Abstract

•

Recovery of insulin sensitivity in obese patients at short term after biliopancreatic diversion. Author(s): Adami GF, Cordera R, Camerini G, Marinari GM, Scopinaro N. Source: The Journal of Surgical Research. 2003 August; 113(2): 217-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957132&dopt=Abstract

•

Reduced expression of the growth hormone and type 1 insulin-like growth factor receptors in human somatotroph tumours and an analysis of possible mutations of the growth hormone receptor. Author(s): Kola B, Korbonits M, Diaz-Cano S, Kaltsas G, Morris DG, Jordan S, Metherell L, Powell M, Czirjak S, Arnaldi G, Bustin S, Boscaro M, Mantero F, Grossman AB. Source: Clinical Endocrinology. 2003 September; 59(3): 328-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919156&dopt=Abstract

•

Regulation of GLUT4 traffic and function by insulin and contraction in skeletal muscle. Author(s): Tremblay F, Dubois MJ, Marette A. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 September 1; 8: D1072-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957810&dopt=Abstract

•

Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Author(s): Stoeltzing O, Liu W, Reinmuth N, Fan F, Parikh AA, Bucana CD, Evans DB, Semenza GL, Ellis LM. Source: American Journal of Pathology. 2003 September; 163(3): 1001-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937141&dopt=Abstract

146 Insulin

•

Regulation of insulin exocytosis by Munc13-1. Author(s): Sheu L, Pasyk EA, Ji J, Huang X, Gao X, Varoqueaux F, Brose N, Gaisano HY. Source: The Journal of Biological Chemistry. 2003 July 25; 278(30): 27556-63. Epub 2003 May 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871971&dopt=Abstract

•

Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention. Author(s): Posner BI. Source: Curr Opin Investig Drugs. 2003 April; 4(4): 430-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808882&dopt=Abstract

•

Regulatory roles for small G proteins in the pancreatic beta-cell: lessons from models of impaired insulin secretion. Author(s): Kowluru A. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E669-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959934&dopt=Abstract

•

Relation between insulin kinetics and insulin sensitivity in pregnancy. Author(s): Jolly MC, Hovorka R, Godsland I, Amin R, Lawrence N, Anyaoku V, Johnston D, Robinson S. Source: European Journal of Clinical Investigation. 2003 August; 33(8): 698-703. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864780&dopt=Abstract

•

Relationship of difficult laryngoscopy to long-term non-insulin-dependent diabetes and hand abnormality detected using the 'prayer sign'. Author(s): Erden V, Basaranoglu G, Delatioglu H, Hamzaoglu NS. Source: British Journal of Anaesthesia. 2003 July; 91(1): 159-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821580&dopt=Abstract

•

Relationships in men of sex hormones, insulin, adiposity, and risk factors for myocardial infarction. Author(s): Phillips GB, Jing T, Heymsfield SB. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 784-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800107&dopt=Abstract

•

Relative impact of insulin resistance and obesity on cardiovascular risk factors in polycystic ovary syndrome. Author(s): Goodarzi MO, Erickson S, Port SC, Jennrich RI, Korenman SG. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 713-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800096&dopt=Abstract

Studies

147

•

Responsibility of insulin to the change of glucose level in newborn small for gestational age infants. Author(s): Feng Q. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2000 March; 15(1): 7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899390&dopt=Abstract

•

Risk of ovarian cancer in relation to prediagnostic levels of C-peptide, insulin-like growth factor binding proteins-1 and -2 (USA, Sweden, Italy). Author(s): Lukanova A, Lundin E, Micheli A, Akhmedkhanov A, Rinaldi S, Muti P, Lenner P, Biessy C, Krogh V, Riboli E, Hallmans G, Berrino F, Zeleniuch-Jacquotte A, Toniolo P, Kaaks R. Source: Cancer Causes & Control : Ccc. 2003 April; 14(3): 285-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814208&dopt=Abstract

•

Role of endothelial dysfunction in insulin resistance. Author(s): Hsueh WA, Quinones MJ. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 10J-17J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957322&dopt=Abstract

•

Role of insulin-like growth factor-1 signaling in dental fibroblast apoptosis. Author(s): Han X, Amar S. Source: J Periodontol. 2003 August; 74(8): 1176-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514231&dopt=Abstract

•

Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly. Author(s): Clemmons DR. Source: Pituitary. 2002; 5(3): 181-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812310&dopt=Abstract

•

Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Author(s): Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Source: Diabetes. 2003 August; 52(8): 1943-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882909&dopt=Abstract

•

Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients. Author(s): HOE 901/2004 Study Investigators Group. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 July; 20(7): 545-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823235&dopt=Abstract

148 Insulin

•

Salt sensitivity is not associated with hyperinsulinaemia in a sample of rural black Zimbabweans. Author(s): Mufunda J, Chifamba J, Chitate N, Vengesa PM. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1998 March; 88(3 Endocrinology): 361-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886697&dopt=Abstract

•

Selective intra-arterial calcium stimulation with hepatic venous sampling for preoperative localization of insulinomas. Author(s): Sung YM, Do YS, Lee MK, Shin SW, Liu WC, Choo SW, Choo IW. Source: Korean Journal of Radiology : Official Journal of the Korean Radiological Society. 2003 April-June; 4(2): 101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845305&dopt=Abstract

•

Self-treatment of mild symptomatic hypoglycaemia by people with insulin-treated diabetes. Author(s): Sommerfield AJ, Ewing FM, Strachan MW, Deary IJ, Aitken G, Frier BM. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 686-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873300&dopt=Abstract

•

Serum concentrations of insulin-like growth factor-I (IGF-I) in patients with liver cirrhosis. Author(s): Vyzantiadis T, Theodoridou S, Giouleme O, Harsoulis P, Evgenidis N, Vyzantiadis A. Source: Hepatogastroenterology. 2003 May-June; 50(51): 814-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828091&dopt=Abstract

•

Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Author(s): Vasan RS, Sullivan LM, D'Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW. Source: Annals of Internal Medicine. 2003 October 21; 139(8): 642-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568852&dopt=Abstract

•

Serum insulin-like growth factor I and subsequent risk of colorectal cancer among Japanese-American men. Author(s): Nomura AM, Stemmermann GN, Lee J, Pollak MN. Source: American Journal of Epidemiology. 2003 September 1; 158(5): 424-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12936897&dopt=Abstract

Studies

149

•

Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Author(s): Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D. Source: Cancer Research. 2003 July 15; 63(14): 3991-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873996&dopt=Abstract

•

Serum levels of insulin-like growth factor-I (IGF-I), and IGF-binding proteins-1 and 3 in middle-aged and young athletes versus sedentary men: relationship with glucose disposal. Author(s): Manetta J, Brun JF, Fedou C, Maimoun L, Prefaut C, Mercier J. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 821-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870155&dopt=Abstract

•

Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. Author(s): Geary MP, Pringle PJ, Rodeck CH, Kingdom JC, Hindmarsh PC. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3708-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915659&dopt=Abstract

•

Sleep-disordered breathing, glucose intolerance, and insulin resistance. Author(s): Punjabi NM, Ahmed MM, Polotsky VY, Beamer BA, O'Donnell CP. Source: Respiratory Physiology & Neurobiology. 2003 July 16; 136(2-3): 167-78. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853008&dopt=Abstract

•

Structural and functional evidence for the interaction of insulin-like growth factors (IGFs) and IGF binding proteins with vitronectin. Author(s): Kricker JA, Towne CL, Firth SM, Herington AC, Upton Z. Source: Endocrinology. 2003 July; 144(7): 2807-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810534&dopt=Abstract

•

Study on the possibility of insulin as a carrier of IUdR for hepatocellular carcinomatargeted therapy. Author(s): Ou XH, Kuang AR, Peng X, Zhong YG. Source: World Journal of Gastroenterology : Wjg. 2003 August; 9(8): 1675-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918099&dopt=Abstract

150 Insulin

•

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. Author(s): Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2738-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788882&dopt=Abstract

•

Sugars, insulin sensitivity, and the postprandial state. Author(s): Daly M. Source: The American Journal of Clinical Nutrition. 2003 October; 78(4): 865S-872S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522751&dopt=Abstract

•

Switching from an oral regimen to insulin in diabetes. Author(s): Perry M. Source: Community Nurse. 2000 May; 6(4): 27-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778520&dopt=Abstract

•

The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients. Author(s): Marini MA, Frontoni S, Mineo D, Bracaglia D, Cardellini M, De Nicolais P, Baroni A, D'Alfonso R, Perna M, Lauro D, Federici M, Gambardella S, Lauro R, Sesti G. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3368-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843189&dopt=Abstract

•

The benefits of glucose-insulin-potassium for acute myocardial infarction (and some concerns). Author(s): Apstein CS. Source: Journal of the American College of Cardiology. 2003 September 3; 42(5): 792-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957422&dopt=Abstract

•

The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Author(s): Hsueh WA, Law R. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 3J-9J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957321&dopt=Abstract

Studies

151

•

The combination of insulin-like growth factor 1 and osteogenic protein 1 promotes increased survival of and matrix synthesis by normal and osteoarthritic human articular chondrocytes. Author(s): Loeser RF, Pacione CA, Chubinskaya S. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2188-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905472&dopt=Abstract

•

The degree of fat saturation does not alter glycemic, insulinemic or satiety responses to a starchy staple in healthy men. Author(s): MacIntosh CG, Holt SH, Brand-Miller JC. Source: The Journal of Nutrition. 2003 August; 133(8): 2577-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888640&dopt=Abstract

•

The effect of metformin on ovarian stimulation and in vitro fertilization in insulinresistant women with polycystic ovary syndrome: an open-label randomized crossover trial. Author(s): Fedorcsak P, Dale PO, Storeng R, Abyholm T, Tanbo T. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 June; 17(3): 207-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857428&dopt=Abstract

•

The effect of the -308A allele of the TNF-alpha gene on insulin action is dependent on obesity. Author(s): Pihlajamaki J, Ylinen M, Karhapaa P, Vauhkonen I, Laakso M. Source: Obesity Research. 2003 July; 11(7): 912-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855762&dopt=Abstract

•

The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Author(s): Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. Source: Rom J Gastroenterol. 2003 September; 12(3): 189-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502318&dopt=Abstract

•

The GP's role in converting patients to insulin. Author(s): McIntyre M. Source: The Practitioner. 2003 July; 247(1648): 582-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879563&dopt=Abstract

152 Insulin

•

The impact of an insulin sensitizer, troglitazone, on glucose metabolism in African Americans at risk for type 2 diabetes mellitus: a placebo-controlled, 24-month randomized study. Author(s): Schuster D, Gaillard T, Rhinesmith S, Habash D, Osei K. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1211-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506629&dopt=Abstract

•

The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Author(s): Suliman AM, Freaney R, Smith TP, McBrinn Y, Murray B, McKenna TJ. Source: Clinical Endocrinology. 2003 September; 59(3): 380-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919163&dopt=Abstract

•

The importance of insulin resistance in polycystic ovary syndrome. Author(s): Goodarzi MO, Korenman SG. Source: Fertility and Sterility. 2003 August; 80(2): 255-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909480&dopt=Abstract

•

The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Author(s): Black PH. Source: Brain, Behavior, and Immunity. 2003 October; 17(5): 350-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946657&dopt=Abstract

•

The insulin resistance syndrome. Author(s): Reaven GM. Source: Current Atherosclerosis Reports. 2003 September; 5(5): 364-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911846&dopt=Abstract

•

The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. Author(s): Juhan-Vague I, Morange PE, Alessi MC. Source: Pathophysiology of Haemostasis and Thrombosis. 2002 September-December; 32(5-6): 269-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679655&dopt=Abstract

Studies

153

•

The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptideregardless of etiology and phenotype. Author(s): Vilsboll T, Knop FK, Krarup T, Johansen A, Madsbad S, Larsen S, Hansen T, Pedersen O, Holst JJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4897-903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557471&dopt=Abstract

•

The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation. Author(s): Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, Rameh LE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 August 19; 100(17): 9867-72. Epub 2003 Aug 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897244&dopt=Abstract

•

The role of intramuscular lipid in insulin resistance. Author(s): Hegarty BD, Furler SM, Ye J, Cooney GJ, Kraegen EW. Source: Acta Physiologica Scandinavica. 2003 August; 178(4): 373-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864742&dopt=Abstract

•

The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. Author(s): Seto-Young D, Zajac J, Liu HC, Rosenwaks Z, Poretsky L. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3385-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843192&dopt=Abstract

•

The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6phosphate/insulin-like growth factor II receptor. Author(s): Di Bacco A, Gill G. Source: Oncogene. 2003 August 21; 22(35): 5436-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934103&dopt=Abstract

•

The surface receptor is involved in annexin I-stimulated insulin secretion in MIN6N8a cells. Author(s): Won JH, Kang NN, Auh CK, Park YM. Source: Biochemical and Biophysical Research Communications. 2003 July 25; 307(2): 389-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859969&dopt=Abstract

154 Insulin

•

The transition from knowing to doing: teaching junior doctors how to use insulin in the management of diabetes mellitus. Author(s): Conn JJ, Dodds AE, Colman PG. Source: Medical Education. 2003 August; 37(8): 689-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12895248&dopt=Abstract

•

The WT1 Wilms' tumor suppressor gene: a novel target for insulin-like growth factorI action. Author(s): Bentov I, LeRoith D, Werner H. Source: Endocrinology. 2003 October; 144(10): 4276-9. Epub 2003 July 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960088&dopt=Abstract

•

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Author(s): Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Kober L, TorpPedersen C. Source: Circulation. 2003 October 14; 108(15): 1815-21. Epub 2003 Oct 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530204&dopt=Abstract

•

Unraveling Reaven's syndrome X: serum insulin-like growth factor-I and cardiovascular disease. Author(s): Malik J, Stulc T, Ceska R. Source: Circulation. 2003 May 27; 107(20): E190-2; Author Reply E190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778906&dopt=Abstract

•

Unraveling Reaven's syndrome X: serum insulin-like growth factor-I and cardiovascular disease. Author(s): Conti E, Crea F, Andreotti F. Source: Circulation. 2003 May 27; 107(20): E190-2; Author Reply E190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778905&dopt=Abstract

•

Unraveling Reaven's syndrome X: serum insulin-like growth factor-I and cardiovascular disease. Author(s): Twickler MT, Cramer MJ, Koppeschaar HP. Source: Circulation. 2003 May 27; 107(20): E190-2; Author Reply E190-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777323&dopt=Abstract

•

Urokinase type plasminogen activator receptor is involved in insulin-like growth factor-induced migration of rhabdomyosarcoma cells in vitro. Author(s): Gallicchio MA, Kaun C, Wojta J, Binder B, Bach LA. Source: Journal of Cellular Physiology. 2003 October; 197(1): 131-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942549&dopt=Abstract

Studies

155

•

Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. Author(s): Tuan CY, Abbasi F, Lamendola C, McLaughlin T, Reaven G. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 606-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943888&dopt=Abstract

•

Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Author(s): Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Source: Epilepsy Research. 2003 June-July; 55(1-2): 53-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948616&dopt=Abstract

•

Vanadate regulates the insulin mitogenic effect by modulating SHP-2 association with insulin receptor substrate 1 in JAr human choriocarcinoma cells. Author(s): Bifulco G, Caruso M, Di Carlo C, Acunzo G, Votino C, Pellicano M, Beguinot F, Nappi C. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 June; 17(3): 239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857432&dopt=Abstract

•

Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population. Author(s): Weedon MN, Turner M, Knight B, Clark P, Hattersley AT, Frayling TM. Source: Clinical Endocrinology. 2003 August; 59(2): 175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864794&dopt=Abstract

•

We should avoid the indiscriminate use of insulin sensitizers in women with polycystic ovary syndrome. Author(s): Azziz R. Source: Fertility and Sterility. 2003 August; 80(2): 264-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909483&dopt=Abstract

•

Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndrome. Author(s): Aubert H, Frere C, Aillaud MF, Morange PE, Juhan-Vague I, Alessi MC. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 April; 1(4): 791-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871417&dopt=Abstract

•

Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes. Author(s): Williams KV, Bertoldo A, Kinahan P, Cobelli C, Kelley DE. Source: Diabetes. 2003 July; 52(7): 1619-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829624&dopt=Abstract

156 Insulin

•

Whole grain intake is associated with lower body mass and greater insulin sensitivity among adolescents. Author(s): Steffen LM, Jacobs DR Jr, Murtaugh MA, Moran A, Steinberger J, Hong CP, Sinaiko AR. Source: American Journal of Epidemiology. 2003 August 1; 158(3): 243-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882946&dopt=Abstract

•

Why do people with diabetes who rely on insulin sometimes behave strangely when their blood sugar is too low? Author(s): Blackburn GL. Source: Health News. 2003 August; 9(8): 12. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971323&dopt=Abstract

157

CHAPTER 2. NUTRITION AND INSULIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and insulin.

Finding Nutrition Studies on Insulin The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “insulin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

158 Insulin

The following is a typical result when searching for recently indexed consumer information on insulin: •

Carbo counting. Author(s): University of Miami School of Medicine, FL. Source: Rafkin Mervis, L.E. Diabetes-forecast (USA). (February 1995). volume 48(2) page 30-37.

•

Fatty acid composition of skeletal muscle membrane phospholipids, insulin resistance and obesity. Author(s): The Center for Genetics, Nutrition and Health, Washington, DC. Source: Simopoulos, A.P. Nutrition-today (USA). (February 1994). volume 29(1) page 1216.

•

Genetic errors that result in diabetes mellitus. Author(s): University of Georgia, Athens. Source: Berdanier, C.D. Nutrition-today (USA). (February 1994). volume 29(1) page 1724.

•

Nutrition considerations in the control of diabetes mellitus. Author(s): Stanford University Medical Center. Source: Coulston, A.M. Nutrition-today (USA). (February 1994). volume 29(1) page 6-11.

•

Pasta-makes-you-fat furor raises question of insulin resistance. Source: Hudnall, M. Environmental-nutrition (USA). (May 1995). volume 18(5) page 1, 4.

•

Sugar replacers: a growing group of sweeteners in the United States. Author(s): Consumer Choices Inc., Winfield, IL. Source: McNutt, K. Sentko, A. Nutrition-today (USA). (December 1996). volume 31(6) page 255-261.

•

The wait is over. Source: McCarren, M. Diabetes-forecast (USA). (August 1996). volume 49(8) page 24-29.

•

The weighting game. Source: Liebman, B. Schardt, D. Nutrition-action-health-letter (USA). (May 1995). volume 22(4) page 1, 4-7.

Additional consumer oriented references include: •

Acarbose improves indirectly both insulin resistance and secretion in obese type 2 diabetic patients. Author(s): Division of Therapeutic Education for Chronic Diseases, University Hospital Geneva, Switzerland. Source: Delgado, H Lehmann, T Bobbioni Harsch, E Ybarra, J Golay, A Diabetes-Metab. 2002 June; 28(3): 195-200 1262-3636

•

Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Author(s): Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, 2900 Hellerup, Denmark. [email protected] Source: Vilsboll, T Krarup, T Madsbad, S Holst, J J Diabetologia. 2002 August; 45(8): 1111-9 0012-186X

Nutrition

159

•

Effect of cholecystokinin-A receptor blockade on postprandial insulinaemia and gastric emptying in humans. Author(s): Department of Surgery, Hospital de Mataro, Mataro, Spain. [email protected] Source: Hidalgo, L Clave, P Estorch, M Rodriguez Espinosa, J Rovati, L Greeley, G H Capella, G Lluis, F Neurogastroenterol-Motil. 2002 October; 14(5): 519-25 1350-1925

•

Effect of insulin, transferrin and selenium and epidermal growth factor on development of buffalo oocytes to the blastocyst stage in vitro in serum-free, semidefined media. Author(s): University of Agricultural Sciences, Hebbal, Bangalore, Karnataka, India. Source: Raghu, H M Nandi, S Reddy, S M Vet-Rec. 2002 August 31; 151(9): 260-5 00424900

•

Effects of glucose-insulin-potassium infusion on chronic ischaemic left ventricular dysfunction. Author(s): University of Queensland, Brisbane, Queensland, Australia. Source: Khoury, V K Haluska, B Prins, J Marwick, T H Heart. 2003 January; 89(1): 61-5 1468-201X

•

Elevated plasma free fatty acid concentrations do not modify cardiac repolarization in patients treated by electrolyte-glucose-insulin infusion. Author(s): Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. Source: Nappo, F Loreto, M Giugliano, G Grella, E Esposito, K Lettieri, B Giugliano, D JEndocrinol-Invest. 2002 Jul-August; 25(7): RC19-22 0391-4097

•

Free fatty acids-the link between obesity and insulin resistance. Author(s): Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. Source: Boden, G Endocr-Pract. 2001 Jan-February; 7(1): 44-51 1530-891X

•

Glucose dependence of insulinotropic actions of pituitary adenylate cyclaseactivating polypeptide in insulin-secreting INS-1 cells. Author(s): Department of Physiological Sciences, Lund University, BMC F11, Tornavagen 10, 221 84 Lund, Sweden. Source: Rosengren, A Filipsson, K Jing, X J Reimer, M K Renstrom, E Pflugers-Arch. 2002 July; 444(4): 556-67 0031-6768

•

Glucose-insulin-potassium solution for acute myocardial infarction. Author(s): Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, New York, NY, USA. Source: Janiger, J L Cheng, J W Ann-Pharmacother. 2002 June; 36(6): 1080-4 1060-0280

•

Glycaemic and insulinaemic responses to a new hydrogenated starch hydrolysate in healthy and type 2 diabetic subjects. Author(s): Department of Diabetes, INSERM U341, Hotel-Dieu Hospital, Paris, France. Source: Rizkalla, S W Luo, J Wils, D Bruzzo, F Slama, G Diabetes-Metab. 2002 November; 28(5): 385-90 1262-3636

•

Hypertension and insulin disorders. Author(s): Division of Internal Medicine, Ajina Tsuchiya Hospital, 4-51-1 Ajina Hatsukaichi, Japan. [email protected] Source: Imazu, M Curr-Hypertens-Repage 2002 December; 4(6): 477-82 1522-6417

160 Insulin

•

Impaired NO-dependent vasodilation in patients with Type II (non-insulindependent) diabetes mellitus is restored by acute administration of folate. Author(s): Department of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Source: van Etten, R W de Koning, E J Verhaar, M C Gaillard, C A Rabelink, T J Diabetologia. 2002 July; 45(7): 1004-10 0012-186X

•

Influence of perfusate calcium concentration on the inotropic insulin effect in isolated guinea pig and rat hearts. Author(s): Institute of Physiology, FUB, Arnimallee 22, 14195 Berlin, Germany. [email protected] Source: Schmidt, H D Koch, M Basic-Res-Cardiol. 2002 July; 97(4): 305-11 0300-8428

•

Insulin effect on leucine kinetics in type 2 diabetes mellitus. Author(s): Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. Source: Halvatsiotis, P G Turk, D Alzaid, A Dinneen, S Rizza, R A Nair, K S DiabetesNutr-Metab. 2002 June; 15(3): 136-42 0394-3402

•

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Author(s): Section of Integrative Physiology, Karolinska Institutet, Stockholm, Sweden. Source: Bjornholm, M Al Khalili, L Dicker, A Naslund, E Rossner, S Zierath, J R Arner, P Diabetologia. 2002 August; 45(8): 1128-35 0012-186X

•

Insulin-mediated tyrosine phosphorylation of myosin heavy chain and concomitant enhanced association of C-terminal SRC kinase during skeletal muscle differentiation. Author(s): Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India. Source: Goel, H L Dey, C S Cell-Biol-Int. 2002; 26(6): 557-61 1065-6995

•

Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms. Author(s): Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA. Source: Lee, J W Romsos, D R Exp-Biol-Med-(Maywood). 2003 February; 228(2): 183-7 1535-3702

•

Leptin constrains phospholipase C-protein kinase C-induced insulin secretion via a phosphatidylinositol 3-kinase-dependent pathway. Author(s): Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA. Source: Lee, J W Swick, A G Romsos, D R Exp-Biol-Med-(Maywood). 2003 February; 228(2): 175-82 1535-3702

•

Long-term effect of fish oil diet on basal and stimulated plasma glucose and insulin levels in ob/ob mice. Author(s): Laboratory for Pathology and Immunobiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. [email protected] Source: Steerenberg, P A Beekhof, P K Feskens, E J Lips, C J Hoppener, J W Beems, R B Diabetes-Nutr-Metab. 2002 August; 15(4): 205-14 0394-3402

Nutrition

161

•

Metabolic characterization of insulin resistance syndrome feature loci in three brown Norway-derived congenic strains. Author(s): Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic. Source: Seda, O Sedova, L Kazdova, L Krenova, D Kren, V Folia-Biol-(Praha). 2002; 48(3): 81-8 0015-5500

•

Optic disc swelling in an adolescent with insulin dependent diabetes mellitus. Author(s): Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia. Source: Fraser Bell, S Capon, M Clin-Experiment-Ophthalmol. 2002 December; 30(6): 434-6 1442-6404

•

Prevalence of hypoglycemia following pre-exercise carbohydrate ingestion is not accompanied By higher insulin sensitivity. Author(s): Human Performance Laboratory, School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK. Source: Jentjens, R L Jeukendrup, A E Int-J-Sport-Nutr-Exerc-Metab. 2002 December; 12(4): 398-413 1526-484X

•

Regulation of muscle malonyl-CoA levels in the nutritionally insulin-resistant desert gerbil, Psammomys obesus. Author(s): Department of Biochemistry and Diabetes Research Unit, Hadassah University Hospital, Jerusalem 91120, Israel. [email protected] Source: Shafrir, E Ziv, E Saha, A K Ruderman, N B Diabetes-Metab-Res-Revolume 2002 May-June; 18(3): 217-23 1520-7552

•

Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion. Author(s): Department of Physiology, Karolinska Institutet, Stockholm, Sweden. Source: Bruton, J D Lemmens, R Shi, C L Persson Sjogren, S Westerblad, H Ahmed, M Pyne, N J Frame, M Furman, B L Islam, M S FASEB-J. 2003 February; 17(2): 301-3 15306860

•

Short-term administration of insulin-like growth factor I (IGF-1) does not induce myocardial IGF-1 resistance. Author(s): Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, ND 58203, USA. [email protected] Source: Ren, J Growth-Horm-IGF-Res. 2002 June; 12(3): 162-8 1096-6374

•

The biomimetic [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+ )decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats. Author(s): Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Source: Sun, Y Clodfelder, B J Shute, A A Irvin, T Vincent, J B J-Biol-Inorg-Chem. 2002 September; 7(7-8): 852-62 0949-8257

•

The effect of combination treatment with acarbose and glibenclamide on postprandial glucose and insulin profiles: additive blood glucose lowering effect and decreased hypoglycaemia. Author(s): Krankenhaus Sachsenhausen, Inn Med, Frankfurt, Germany. Source: Rosak, C Haupt, E Walter, T Werner, J Diabetes-Nutr-Metab. 2002 June; 15(3): 143-51 0394-3402

162 Insulin

•

The role of coping with disease in adherence to treatment regimen and disease control in type 1 and insulin treated type 2 diabetes mellitus. Author(s): Davranis Bilimleri Enstitusu (Institute for Behavioral Studies), Istanbul. [email protected] Source: Turan, B Osar, Z Molzan Turan, J Damci, T Ilkova, H Diabetes-Metab. 2002 June; 28(3): 186-93 1262-3636

•

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men. Author(s): The Lipid and Arteriosclerosis Research Unit, Reina Sofia University Hospital, Medical School, University of Cordoba, Spain. [email protected] Source: Perez Jimenez, F Lopez Miranda, J Gomez, P Velasco, M J Marin, C Perez Martinez, P Moreno, J A Paniagua, J A Diabetologia. 2002 August; 45(8): 1196-200 0012186X

•

Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Author(s): Department of Surgery, McGill University Health Center, The Royal Victoria Hospital, Montreal, Quebec, Canada. Source: Zhang, D Brodt, P Oncogene. 2003 February 20; 22(7): 974-82 0950-9232

•

Vascular function, insulin resistance and fatty acids. Author(s): Indiana University School of Medicine, Indianapolis, USA. Source: Steinberg, H O Baron, A D Diabetologia. 2002 May; 45(5): 623-34 0012-186X

•

When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus. Author(s): Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, New York 10019, USA. Source: Langer, O J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 218-25 1476-7058

The following information is typical of that found when using the “Full IBIDS Database” to search for “insulin” (or a synonym): •

Acarbose improves indirectly both insulin resistance and secretion in obese type 2 diabetic patients. Author(s): Division of Therapeutic Education for Chronic Diseases, University Hospital Geneva, Switzerland. Source: Delgado, H Lehmann, T Bobbioni Harsch, E Ybarra, J Golay, A Diabetes-Metab. 2002 June; 28(3): 195-200 1262-3636

•

Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Author(s): Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, 2900 Hellerup, Denmark. [email protected] Source: Vilsboll, T Krarup, T Madsbad, S Holst, J J Diabetologia. 2002 August; 45(8): 1111-9 0012-186X

•

Effect of cholecystokinin-A receptor blockade on postprandial insulinaemia and gastric emptying in humans. Author(s): Department of Surgery, Hospital de Mataro, Mataro, Spain. [email protected] Source: Hidalgo, L Clave, P Estorch, M Rodriguez Espinosa, J Rovati, L Greeley, G H Capella, G Lluis, F Neurogastroenterol-Motil. 2002 October; 14(5): 519-25 1350-1925

Nutrition

163

•

Effect of insulin, transferrin and selenium and epidermal growth factor on development of buffalo oocytes to the blastocyst stage in vitro in serum-free, semidefined media. Author(s): University of Agricultural Sciences, Hebbal, Bangalore, Karnataka, India. Source: Raghu, H M Nandi, S Reddy, S M Vet-Rec. 2002 August 31; 151(9): 260-5 00424900

•

Effects of glucose-insulin-potassium infusion on chronic ischaemic left ventricular dysfunction. Author(s): University of Queensland, Brisbane, Queensland, Australia. Source: Khoury, V K Haluska, B Prins, J Marwick, T H Heart. 2003 January; 89(1): 61-5 1468-201X

•

Elevated plasma free fatty acid concentrations do not modify cardiac repolarization in patients treated by electrolyte-glucose-insulin infusion. Author(s): Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. Source: Nappo, F Loreto, M Giugliano, G Grella, E Esposito, K Lettieri, B Giugliano, D JEndocrinol-Invest. 2002 Jul-August; 25(7): RC19-22 0391-4097

•

Free fatty acids-the link between obesity and insulin resistance. Author(s): Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. Source: Boden, G Endocr-Pract. 2001 Jan-February; 7(1): 44-51 1530-891X

•

Glucose dependence of insulinotropic actions of pituitary adenylate cyclaseactivating polypeptide in insulin-secreting INS-1 cells. Author(s): Department of Physiological Sciences, Lund University, BMC F11, Tornavagen 10, 221 84 Lund, Sweden. Source: Rosengren, A Filipsson, K Jing, X J Reimer, M K Renstrom, E Pflugers-Arch. 2002 July; 444(4): 556-67 0031-6768

•

Glucose-insulin-potassium solution for acute myocardial infarction. Author(s): Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, New York, NY, USA. Source: Janiger, J L Cheng, J W Ann-Pharmacother. 2002 June; 36(6): 1080-4 1060-0280

•

Glycaemic and insulinaemic responses to a new hydrogenated starch hydrolysate in healthy and type 2 diabetic subjects. Author(s): Department of Diabetes, INSERM U341, Hotel-Dieu Hospital, Paris, France. Source: Rizkalla, S W Luo, J Wils, D Bruzzo, F Slama, G Diabetes-Metab. 2002 November; 28(5): 385-90 1262-3636

•

Hypertension and insulin disorders. Author(s): Division of Internal Medicine, Ajina Tsuchiya Hospital, 4-51-1 Ajina Hatsukaichi, Japan. [email protected] Source: Imazu, M Curr-Hypertens-Repage 2002 December; 4(6): 477-82 1522-6417

•

Impaired NO-dependent vasodilation in patients with Type II (non-insulindependent) diabetes mellitus is restored by acute administration of folate. Author(s): Department of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Source: van Etten, R W de Koning, E J Verhaar, M C Gaillard, C A Rabelink, T J Diabetologia. 2002 July; 45(7): 1004-10 0012-186X

164 Insulin

•

Influence of perfusate calcium concentration on the inotropic insulin effect in isolated guinea pig and rat hearts. Author(s): Institute of Physiology, FUB, Arnimallee 22, 14195 Berlin, Germany. [email protected] Source: Schmidt, H D Koch, M Basic-Res-Cardiol. 2002 July; 97(4): 305-11 0300-8428

•

Insulin effect on leucine kinetics in type 2 diabetes mellitus. Author(s): Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. Source: Halvatsiotis, P G Turk, D Alzaid, A Dinneen, S Rizza, R A Nair, K S DiabetesNutr-Metab. 2002 June; 15(3): 136-42 0394-3402

•

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Author(s): Section of Integrative Physiology, Karolinska Institutet, Stockholm, Sweden. Source: Bjornholm, M Al Khalili, L Dicker, A Naslund, E Rossner, S Zierath, J R Arner, P Diabetologia. 2002 August; 45(8): 1128-35 0012-186X

•

Insulin-mediated tyrosine phosphorylation of myosin heavy chain and concomitant enhanced association of C-terminal SRC kinase during skeletal muscle differentiation. Author(s): Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India. Source: Goel, H L Dey, C S Cell-Biol-Int. 2002; 26(6): 557-61 1065-6995

•

Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms. Author(s): Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA. Source: Lee, J W Romsos, D R Exp-Biol-Med-(Maywood). 2003 February; 228(2): 183-7 1535-3702

•

Leptin constrains phospholipase C-protein kinase C-induced insulin secretion via a phosphatidylinositol 3-kinase-dependent pathway. Author(s): Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA. Source: Lee, J W Swick, A G Romsos, D R Exp-Biol-Med-(Maywood). 2003 February; 228(2): 175-82 1535-3702

•

Long-term effect of fish oil diet on basal and stimulated plasma glucose and insulin levels in ob/ob mice. Author(s): Laboratory for Pathology and Immunobiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. [email protected] Source: Steerenberg, P A Beekhof, P K Feskens, E J Lips, C J Hoppener, J W Beems, R B Diabetes-Nutr-Metab. 2002 August; 15(4): 205-14 0394-3402

•

Metabolic characterization of insulin resistance syndrome feature loci in three brown Norway-derived congenic strains. Author(s): Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic. Source: Seda, O Sedova, L Kazdova, L Krenova, D Kren, V Folia-Biol-(Praha). 2002; 48(3): 81-8 0015-5500

Nutrition

165

•

Optic disc swelling in an adolescent with insulin dependent diabetes mellitus. Author(s): Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia. Source: Fraser Bell, S Capon, M Clin-Experiment-Ophthalmol. 2002 December; 30(6): 434-6 1442-6404

•

Prevalence of hypoglycemia following pre-exercise carbohydrate ingestion is not accompanied By higher insulin sensitivity. Author(s): Human Performance Laboratory, School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK. Source: Jentjens, R L Jeukendrup, A E Int-J-Sport-Nutr-Exerc-Metab. 2002 December; 12(4): 398-413 1526-484X

•

Regulation of muscle malonyl-CoA levels in the nutritionally insulin-resistant desert gerbil, Psammomys obesus. Author(s): Department of Biochemistry and Diabetes Research Unit, Hadassah University Hospital, Jerusalem 91120, Israel. [email protected] Source: Shafrir, E Ziv, E Saha, A K Ruderman, N B Diabetes-Metab-Res-Revolume 2002 May-June; 18(3): 217-23 1520-7552

•

Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion. Author(s): Department of Physiology, Karolinska Institutet, Stockholm, Sweden. Source: Bruton, J D Lemmens, R Shi, C L Persson Sjogren, S Westerblad, H Ahmed, M Pyne, N J Frame, M Furman, B L Islam, M S FASEB-J. 2003 February; 17(2): 301-3 15306860

•

Short-term administration of insulin-like growth factor I (IGF-1) does not induce myocardial IGF-1 resistance. Author(s): Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, ND 58203, USA. [email protected] Source: Ren, J Growth-Horm-IGF-Res. 2002 June; 12(3): 162-8 1096-6374

•

The biomimetic [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+ )decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats. Author(s): Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Source: Sun, Y Clodfelder, B J Shute, A A Irvin, T Vincent, J B J-Biol-Inorg-Chem. 2002 September; 7(7-8): 852-62 0949-8257

•

The effect of combination treatment with acarbose and glibenclamide on postprandial glucose and insulin profiles: additive blood glucose lowering effect and decreased hypoglycaemia. Author(s): Krankenhaus Sachsenhausen, Inn Med, Frankfurt, Germany. Source: Rosak, C Haupt, E Walter, T Werner, J Diabetes-Nutr-Metab. 2002 June; 15(3): 143-51 0394-3402

•

The role of coping with disease in adherence to treatment regimen and disease control in type 1 and insulin treated type 2 diabetes mellitus. Author(s): Davranis Bilimleri Enstitusu (Institute for Behavioral Studies), Istanbul. [email protected] Source: Turan, B Osar, Z Molzan Turan, J Damci, T Ilkova, H Diabetes-Metab. 2002 June; 28(3): 186-93 1262-3636

166 Insulin

•

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men. Author(s): The Lipid and Arteriosclerosis Research Unit, Reina Sofia University Hospital, Medical School, University of Cordoba, Spain. [email protected] Source: Perez Jimenez, F Lopez Miranda, J Gomez, P Velasco, M J Marin, C Perez Martinez, P Moreno, J A Paniagua, J A Diabetologia. 2002 August; 45(8): 1196-200 0012186X

•

Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Author(s): Department of Surgery, McGill University Health Center, The Royal Victoria Hospital, Montreal, Quebec, Canada. Source: Zhang, D Brodt, P Oncogene. 2003 February 20; 22(7): 974-82 0950-9232

•

Vascular function, insulin resistance and fatty acids. Author(s): Indiana University School of Medicine, Indianapolis, USA. Source: Steinberg, H O Baron, A D Diabetologia. 2002 May; 45(5): 623-34 0012-186X

•

When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus. Author(s): Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, New York 10019, USA. Source: Langer, O J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 218-25 1476-7058

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

•

The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

•

The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

•

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

•

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

•

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

•

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

•

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Nutrition

167

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

•

Google: http://directory.google.com/Top/Health/Nutrition/

•

Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

•

Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

•

WebMD®Health: http://my.webmd.com/nutrition

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to insulin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Niacin Alternative names: Vitamin B3 (Niacin) Source: Integrative Medicine Communications; www.drkoop.com Niacin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,892,00.html Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B12 (Cobalamin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (Niacin) Alternative names: Niacin Source: Integrative Medicine Communications; www.drkoop.com Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com

168 Insulin

Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com •

Minerals Biotin Source: Healthnotes, Inc.; www.healthnotes.com Biotin Source: Integrative Medicine Communications; www.drkoop.com Biotin Source: Prima Communications, Inc.www.personalhealthzone.com Biotin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10008,00.html Calcium Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Integrative Medicine Communications; www.drkoop.com Chromium Source: Prima Communications, Inc.www.personalhealthzone.com Chromium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10018,00.html HMG-COA Reductase Inhibitors (Statins) Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com

Nutrition

169

Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Magnesium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,890,00.html Manganese Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Integrative Medicine Communications; www.drkoop.com Sulfur Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Alternative names: Vanadate, Vanadyl Source: Integrative Medicine Communications; www.drkoop.com Vanadium Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin H (Biotin) Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Prima Communications, Inc.www.personalhealthzone.com Zinc Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10071,00.html •

Food and Diet Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com Atkins Diet Source: Healthnotes, Inc.; www.healthnotes.com Burdock Source: Prima Communications, Inc.www.personalhealthzone.com

170 Insulin

Cinnamon Alternative names: Cinnamomum zeylanicum Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Source: Healthnotes, Inc.; www.healthnotes.com High-Fiber Diet Source: Healthnotes, Inc.; www.healthnotes.com Hypoglycemia Source: Healthnotes, Inc.; www.healthnotes.com Low-Fat Diet Source: Healthnotes, Inc.; www.healthnotes.com Low-Purine Diet Source: Healthnotes, Inc.; www.healthnotes.com Low-Salt Diet Source: Healthnotes, Inc.; www.healthnotes.com Natural Sweeteners Source: Healthnotes, Inc.; www.healthnotes.com Nutritional Yeast Source: Integrative Medicine Communications; www.drkoop.com Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com Omega-3 Fatty Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,992,00.html Sprains and Strains Source: Healthnotes, Inc.; www.healthnotes.com The Zone Diet Source: Healthnotes, Inc.; www.healthnotes.com Weight Loss and Obesity Source: Healthnotes, Inc.; www.healthnotes.com

171

CHAPTER 3. ALTERNATIVE MEDICINE AND INSULIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to insulin. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to insulin and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “insulin” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to insulin: •

A combined high-fiber, low-glycemic index diet normalizes glucose tolerance and reduces hyperglycemia and hyperinsulinemia in adults with hepatic cirrhosis. Author(s): Barkoukis H, Fiedler KM, Lerner E. Source: Journal of the American Dietetic Association. 2002 October; 102(10): 1503-7; Discussion 1507-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396175&dopt=Abstract

•

A fermentation product of Cordyceps sinensis increases whole-body insulin sensitivity in rats. Author(s): Balon TW, Jasman AP, Zhu JS. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2002 June; 8(3): 315-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165189&dopt=Abstract

172 Insulin

•

A randomized controlled trial of octreotide pamoate long-acting release and carboplatin versus carboplatin alone in dogs with naturally occurring osteosarcoma: evaluation of insulin-like growth factor suppression and chemotherapy. Author(s): Khanna C, Prehn J, Hayden D, Cassaday RD, Caylor J, Jacob S, Bose SM, Hong SH, Hewitt SM, Helman LJ. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2002 July; 8(7): 2406-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12114446&dopt=Abstract

•

Age-related changes in cortical bone content of insulin-like growth factor binding protein (IGFBP)-3, IGFBP-5, osteoprotegerin, and calcium in postmenopausal osteoporosis: a cross-sectional study. Author(s): Ueland T, Brixen K, Mosekilde L, Mosekilde L, Flyvbjerg A, Bollerslev J. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 10148. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629078&dopt=Abstract

•

Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine. Author(s): Wright JR Jr. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 December 10; 167(12): 1391-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473641&dopt=Abstract

•

Anti-obesity effects of a mixture of thiamin, arginine, caffeine, and citric acid in noninsulin dependent diabetic KK mice. Author(s): Muroyama K, Murosaki S, Yamamoto Y, Odaka H, Chung HC, Miyoshi M. Source: J Nutr Sci Vitaminol (Tokyo). 2003 February; 49(1): 56-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882397&dopt=Abstract

•

Antioxidant effects of Gongronema latifolium in hepatocytes of rat models of noninsulin dependent diabetes mellitus. Author(s): Ugochukwu NH, Babady NE. Source: Fitoterapia. 2002 December; 73(7-8): 612-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490219&dopt=Abstract

•

Association of the fatty acid profile of serum lipids with glucose and insulin metabolism during 2 fat-modified diets in subjects with impaired glucose tolerance. Author(s): Louheranta AM, Sarkkinen ES, Vidgren HM, Schwab US, Uusitupa MI. Source: The American Journal of Clinical Nutrition. 2002 August; 76(2): 331-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145003&dopt=Abstract

Alternative Medicine 173

•

Beta-cell crosstalk: a further dimension in the stimulus-secretion coupling of glucoseinduced insulin release. Author(s): Caton D, Calabrese A, Mas C, Serre-Beinier V, Wonkam A, Meda P. Source: Diabetes & Metabolism. 2002 December; 28(6 Pt 2): 3S45-53; Discussion 3S108-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12688633&dopt=Abstract

•

Chemosensitization of human prostate cancer using antisense agents targeting the type 1 insulin-like growth factor receptor. Author(s): Hellawell GO, Ferguson DJ, Brewster SF, Macaulay VM. Source: Bju International. 2003 February; 91(3): 271-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12581018&dopt=Abstract

•

Chinese medicine, Jiang-Tang-Ke-Li, improves insulin resistance by modulating muscle fiber composition and muscle tumor necrosis factor-alpha in fructose-fed rats. Author(s): Wang L, Higashiura K, Ura N, Miura T, Shimamoto K. Source: Hypertens Res. 2003 July; 26(7): 527-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924619&dopt=Abstract

•

Comparison of effects of different anticoagulants and sample handling procedures on rat insulin radioimmunoassay. Author(s): Iglesias R, Villarroya F, Alemany M. Source: Comp Biochem Physiol A. 1985; 82(4): 863-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14575037&dopt=Abstract

•

Comparison of the effects of dried peas with those of potatoes in mixed meals on postprandial glucose and insulin concentrations in patients with type 2 diabetes. Author(s): Schafer G, Schenk U, Ritzel U, Ramadori G, Leonhardt U. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 99-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816777&dopt=Abstract

•

Comparison of the extrapancreatic action of gamma-linolenic acid and n-3 PUFAs in the high fat diet-induced insulin resistance. Author(s): Simoncikova P, Wein S, Gasperikova D, Ukropec J, Certik M, Klimes I, Sebokova E. Source: Endocrine Regulations. 2002 November; 36(4): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466014&dopt=Abstract

•

CordyMax Cs-4 improves glucose metabolism and increases insulin sensitivity in normal rats. Author(s): Zhao CS, Yin WT, Wang JY, Zhang Y, Yu H, Cooper R, Smidt C, Zhu JS.

174 Insulin

Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2002 June; 8(3): 309-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165188&dopt=Abstract •

Creatine supplementation affects glucose homeostasis but not insulin secretion in humans. Author(s): Rooney KB, Bryson JM, Digney AL, Rae CD, Thompson CH. Source: Annals of Nutrition & Metabolism. 2003; 47(1): 11-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624482&dopt=Abstract

•

Daily profiles of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin, and of pituitary PRL mRNA and GH mRNA in male long evans rats in acute phase of adjuvant arthritis. Author(s): Roman O, Seres J, Herichova I, Zeman M, Jurcovicova J. Source: Chronobiology International. 2003 September; 20(5): 823-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14535356&dopt=Abstract

•

Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. Author(s): Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, Miyamoto S, Nakano M, Ogawa H. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3190-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843164&dopt=Abstract

•

Dietary (n-3) polyunsaturated fatty acids up-regulate plasma leptin in insulinresistant rats. Author(s): Peyron-Caso E, Taverna M, Guerre-Millo M, Veronese A, Pacher N, Slama G, Rizkalla SW. Source: The Journal of Nutrition. 2002 August; 132(8): 2235-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163668&dopt=Abstract

•

Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Author(s): Chen J, Stavro PM, Thompson LU. Source: Nutrition and Cancer. 2002; 43(2): 187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588699&dopt=Abstract

•

Dietary soy and fats in relation to serum insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 levels in premenopausal Japanese women. Author(s): Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K.

Alternative Medicine 175

Source: Nutrition and Cancer. 2003; 45(2): 185-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881012&dopt=Abstract •

Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. Author(s): Clement L, Poirier H, Niot I, Bocher V, Guerre-Millo M, Krief S, Staels B, Besnard P. Source: Journal of Lipid Research. 2002 September; 43(9): 1400-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12235171&dopt=Abstract

•

Effect of chronic treatment with Enicostemma littorale in non-insulin-dependent diabetic (NIDDM) rats. Author(s): Murali B, Upadhyaya UM, Goyal RK. Source: Journal of Ethnopharmacology. 2002 July; 81(2): 199-204. Erratum In: J Ethnopharmacol. 2003 April; 85(2-3): 299. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065151&dopt=Abstract

•

Effect of cogent db, a herbal drug, on plasma insulin and hepatic enzymes of glucose metabolism in experimental diabetes. Author(s): Saravanan G, Pari L, Venkateswaran S. Source: Diabetes, Obesity & Metabolism. 2002 November; 4(6): 394-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406037&dopt=Abstract

•

Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Author(s): Roberts CK, Vaziri ND, Barnard RJ. Source: Circulation. 2002 November 12; 106(20): 2530-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427646&dopt=Abstract

•

Effect of diet and exercise on serum insulin, IGF-I, and IGFBP-1 levels and growth of LNCaP cells in vitro (United States). Author(s): Ngo TH, Barnard RJ, Tymchuk CN, Cohen P, Aronson WJ. Source: Cancer Causes & Control : Ccc. 2002 December; 13(10): 929-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588089&dopt=Abstract

•

Effect of diets enriched in almonds on insulin action and serum lipids in adults with normal glucose tolerance or type 2 diabetes. Author(s): Lovejoy JC, Most MM, Lefevre M, Greenway FL, Rood JC. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1000-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12399271&dopt=Abstract

176 Insulin

•

Effect of Garcinia cambogia extract on serum leptin and insulin in mice. Author(s): Hayamizu K, Hirakawa H, Oikawa D, Nakanishi T, Takagi T, Tachibana T, Furuse M. Source: Fitoterapia. 2003 April; 74(3): 267-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727492&dopt=Abstract

•

Effect of glucose/insulin infusion and magnesium supplementation on serum and muscle sodium and potassium and muscle [3H]ouabain binding capacity in Type 1 diabetes mellitus. Author(s): Djurhuus MS, Klitgaard NA, Pedersen KK. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2003; 63(2): 93102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751690&dopt=Abstract

•

Effect of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che-Sen-Qi-Wan) on insulin resistance in streptozotocin-induced diabetic rats. Author(s): Hu X, Sato J, Oshida Y, Xu M, Bajotto G, Sato Y. Source: Diabetes Research and Clinical Practice. 2003 February; 59(2): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560159&dopt=Abstract

•

Effect of Gymnema montanum on blood glucose, plasma insulin, and carbohydrate metabolic enzymes in alloxan-induced diabetic rats. Author(s): Ananthan R, Latha M, Pari L, Ramkumar KM, Baskar CG, Bai VN. Source: Journal of Medicinal Food. 2003 Spring; 6(1): 43-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804019&dopt=Abstract

•

Effect of isocaloric low-fat diet on human LAPC-4 prostate cancer xenografts in severe combined immunodeficient mice and the insulin-like growth factor axis. Author(s): Ngo TH, Barnard RJ, Cohen P, Freedland S, Tran C, deGregorio F, Elshimali YI, Heber D, Aronson WJ. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2734-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855654&dopt=Abstract

•

Effect of soluble dietary fibre fraction of Trigonella foenum graecum on glycemic, insulinemic, lipidemic and platelet aggregation status of Type 2 diabetic model rats. Author(s): Hannan JM, Rokeya B, Faruque O, Nahar N, Mosihuzzaman M, Azad Khan AK, Ali L. Source: Journal of Ethnopharmacology. 2003 September; 88(1): 73-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902054&dopt=Abstract

•

Effect of source of energy and rate of growth on performance, carcass characteristics, ruminal fermentation, and serum glucose and insulin of early-weaned steers.

Alternative Medicine 177

Author(s): Schoonmaker JP, Cecava VM, Faulkner DB, Fluharty FL, Zerby HN, Loerch SC. Source: Journal of Animal Science. 2003 April; 81(4): 843-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723071&dopt=Abstract •

Effect of structured group education on glycemic control and hypoglycemia in insulin-treated patients. Author(s): Koev DJ, Tankova TI, Kozlovski PG. Source: Diabetes Care. 2003 January; 26(1): 251. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502698&dopt=Abstract

•

Effects of diets enriched in saturated (palmitic), monounsaturated (oleic), or trans (elaidic) fatty acids on insulin sensitivity and substrate oxidation in healthy adults. Author(s): Lovejoy JC, Smith SR, Champagne CM, Most MM, Lefevre M, DeLany JP, Denkins YM, Rood JC, Veldhuis J, Bray GA. Source: Diabetes Care. 2002 August; 25(8): 1283-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145222&dopt=Abstract

•

Effects of glucagon and insulin on plasma glucose, triglyceride, and triglyceride-rich lipoprotein concentrations in laying hens fed diets containing different types of fats. Author(s): Pal L, Grossmann R, Dublecz K, Husveth F, Wagner L, Bartos A, Kovacs G. Source: Poultry Science. 2002 November; 81(11): 1694-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455597&dopt=Abstract

•

Effects of goshajinkigan on corneal sensitivity, superficial punctate keratopathy and tear secretion in patients with insulin-dependent diabetes mellitus. Author(s): Nagaki Y, Hayasaka S, Hayasaka Y, Kadoi C, Sekiya N, Terasawa K, Sakakibara I. Source: The American Journal of Chinese Medicine. 2003; 31(1): 103-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723759&dopt=Abstract

•

Effects of keishi-ka-jutsubu-to (traditional herbal medicine: Gui-zhi-jia-shu-fu-tang) on in vivo insulin action in streptozotocin-induced diabetic rats. Author(s): Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Source: Life Sciences. 2003 October 10; 73(21): 2687-701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679237&dopt=Abstract

•

Effects of konjac extract on insulin sensitivity in high fat diet rats. Author(s): Mao CP, Xie ML, Gu ZL. Source: Acta Pharmacologica Sinica. 2002 September; 23(9): 855-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12230958&dopt=Abstract

178 Insulin

•

Effects of supplementation with purified red clover (Trifolium pratense) isoflavones on plasma lipids and insulin resistance in healthy premenopausal women. Author(s): Blakesmith SJ, Lyons-Wall PM, George C, Joannou GE, Petocz P, Samman S. Source: The British Journal of Nutrition. 2003 April; 89(4): 467-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654164&dopt=Abstract

•

Estimation of plasma insulin from plasma glucose. Author(s): Neatpisarnvanit C, Boston JR. Source: Ieee Transactions on Bio-Medical Engineering. 2002 November; 49(11): 1253-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12450355&dopt=Abstract

•

Estrogen and insulin crosstalk: breast cancer risk implications. Author(s): McCance KL, Jones RE. Source: The Nurse Practitioner. 2003 May; 28(5): 12-23; Quiz 24-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792265&dopt=Abstract

•

Ethyl icosapentate (omega-3 fatty acid) causes accumulation of lipids in skeletal muscle but suppresses insulin resistance in OLETF rats. Otsuka Long-Evans Tokushima Fatty. Author(s): Kusunoki M, Tsutsumi K, Hara T, Ogawa H, Nakamura T, Miyata T, Sakakibara F, Fukuzawa Y, Suga T, Kato K, Hirooka Y, Nakaya Y. Source: Metabolism: Clinical and Experimental. 2003 January; 52(1): 30-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524659&dopt=Abstract

•

Exercise training improves insulin stimulated skeletal muscle glucose uptake independent of changes in perfusion in patients with dilated cardiomyopathy. Author(s): Kemppainen J, Stolen K, Kalliokoski KK, Salo T, Karanko H, Viljanen T, Airaksinen J, Nuutila P, Knuuti J. Source: Journal of Cardiac Failure. 2003 August; 9(4): 286-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680549&dopt=Abstract

•

Extract of Ocimum canum lowers blood glucose and facilitates insulin release by isolated pancreatic beta-islet cells. Author(s): Nyarko AK, Asare-Anane H, Ofosuhene M, Addy ME. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2002 May; 9(4): 346-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120816&dopt=Abstract

•

Garlic extract methylallyl thiosulfinate blocks insulin potentiation of platelet-derived growth factor-stimulated migration of vascular smooth muscle cells. Author(s): Golovchenko I, Yang CH, Goalstone ML, Draznin B.

Alternative Medicine 179

Source: Metabolism: Clinical and Experimental. 2003 February; 52(2): 254-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601642&dopt=Abstract •

GH-Stimulated Insulin-Like Growth Factor I Gene Expression is Mediated by a Tyrosine phosphorylation Pathway Depending on C-terminal Region of Human GH Receptor in Human GH Receptor-Expressing Ba/F3 Cells. Author(s): Yoshizato H, Tanaka M, Nakai N, Nakao N, Nakashima K. Source: Endocrinology. 2003 October 9 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551225&dopt=Abstract

•

Glucose and insulin responses to dietary chromium supplements: a meta-analysis. Author(s): Althuis MD, Jordan NE, Ludington EA, Wittes JT. Source: The American Journal of Clinical Nutrition. 2002 July; 76(1): 148-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12081828&dopt=Abstract

•

Glycemic and insulinemic responses to energy bars of differing macronutrient composition in healthy adults. Author(s): Hertzler SR, Kim Y. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 February; 9(2): Cr84-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601292&dopt=Abstract

•

High-dose calcium stimulation test in a case of insulinoma masquerading as hysteria. Author(s): Nakamura Y, Doi R, Kohno Y, Shimono D, Kuwamura N, Inoue K, Koshiyama H, Imamura M. Source: Endocrine. 2002 November; 19(2): 127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588041&dopt=Abstract

•

High-dose glucose-insulin-potassium after cardiac surgery: a retrospective analysis of clinical safety issues. Author(s): Szabo Z, Hakanson E, Maros T, Svedjeholm R. Source: Acta Anaesthesiologica Scandinavica. 2003 April; 47(4): 383-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694134&dopt=Abstract

•

High-fiber rye bread and insulin secretion and sensitivity in healthy postmenopausal women. Author(s): Juntunen KS, Laaksonen DE, Poutanen KS, Niskanen LK, Mykkanen HM. Source: The American Journal of Clinical Nutrition. 2003 February; 77(2): 385-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540398&dopt=Abstract

•

Hypertrophy of cultured adult rat ventricular cardiomyocytes induced by antibodies against the insulin-like growth factor (IGF)-I or the IGF-I receptor is IGF-II-

180 Insulin

dependent. Author(s): Huang CY, Hao LY, Buetow DE. Source: Molecular and Cellular Biochemistry. 2002 April; 233(1-2): 65-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083381&dopt=Abstract •

Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Author(s): Xu HB, Huang KX, Zhu YS, Gao QH, Wu QZ, Tian WQ, Sheng XQ, Chen ZX, Gao ZH. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2002 November; 46(5): 459-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12419651&dopt=Abstract

•

Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy. Author(s): Behrens GM, Boerner AR, Weber K, van den Hoff J, Ockenga J, Brabant G, Schmidt RE. Source: The Journal of Clinical Investigation. 2002 November; 110(9): 1319-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417571&dopt=Abstract

•

Increase of insulin sensitivity in diabetic rats received die-huang-wan, a herbal mixture used in Chinese traditional medicine. Author(s): Wu YC, Hsu JH, Liu IM, Liou SS, Su HC, Cheng JT. Source: Acta Pharmacologica Sinica. 2002 December; 23(12): 1181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466058&dopt=Abstract

•

Induction of insulin secretion by a component of Urtica dioica leave extract in perifused Islets of Langerhans and its in vivo effects in normal and streptozotocin diabetic rats. Author(s): Farzami B, Ahmadvand D, Vardasbi S, Majin FJ, Khaghani Sh. Source: Journal of Ethnopharmacology. 2003 November; 89(1): 47-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522431&dopt=Abstract

•

Influence of phytostanol phosphoryl ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. Author(s): Wasan KM, Zamfir C, Pritchard PH, Pederson RA. Source: Journal of Pharmaceutical Sciences. 2003 February; 92(2): 281-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532378&dopt=Abstract

•

Insulin- and exercise-stimulated skeletal muscle blood flow and glucose uptake in obese men. Author(s): Hallsten K, Yki-Jarvinen H, Peltoniemi P, Oikonen V, Takala T, Kemppainen J, Laine H, Bergman J, Bolli GB, Knuuti J, Nuutila P.

Alternative Medicine 181

Source: Obesity Research. 2003 February; 11(2): 257-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582222&dopt=Abstract •

Insulin promotes formation of polymerized microtubules by a phosphatidylinositol 3-kinase-independent, actin-dependent pathway in 3T3-L1 adipocytes. Author(s): Olson AL, Eyster CA, Duggins QS, Knight JB. Source: Endocrinology. 2003 November; 144(11): 5030-9. Epub 2003 August 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959978&dopt=Abstract

•

Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Author(s): Luiken JJ, Koonen DP, Willems J, Zorzano A, Becker C, Fischer Y, Tandon NN, Van Der Vusse GJ, Bonen A, Glatz JF. Source: Diabetes. 2002 October; 51(10): 3113-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351456&dopt=Abstract

•

Insulin: discovery and controversy. Author(s): Rosenfeld L. Source: Clinical Chemistry. 2002 December; 48(12): 2270-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446492&dopt=Abstract

•

Insulin-like growth factor I (IGF-1) supplementation prevents diabetes-induced alterations in coenzymes Q9 and Q10. Author(s): Wold LE, Muralikrishnan D, Albano CB, Norby FL, Ebadi M, Ren J. Source: Acta Diabetologica. 2003 June; 40(2): 85-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861406&dopt=Abstract

•

Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: possible mediators for the effects of diet and exercise on cancer cell survival. Author(s): Ngo TH, Barnard RJ, Leung PS, Cohen P, Aronson WJ. Source: Endocrinology. 2003 June; 144(6): 2319-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746292&dopt=Abstract

•

Insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) modulate tenascin-C and fibrillin-1 in bullous keratopathy stromal cells in vitro. Author(s): Kenney MC, Zorapapel N, Atilano S, Chwa M, Ljubimov A, Brown D. Source: Experimental Eye Research. 2003 November; 77(5): 537-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550395&dopt=Abstract

•

Insulin-mediated hepatic glucose uptake is impaired in type 2 diabetes: evidence for a relationship with glycemic control.

182 Insulin

Author(s): Iozzo P, Hallsten K, Oikonen V, Virtanen KA, Kemppainen J, Solin O, Ferrannini E, Knuuti J, Nuutila P. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 2055-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727954&dopt=Abstract •

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Author(s): Beysen C, Karpe F, Fielding BA, Clark A, Levy JC, Frayn KN. Source: Diabetologia. 2002 November; 45(11): 1533-41. Epub 2002 October 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12436337&dopt=Abstract

•

Long-term effect of fish oil diet on basal and stimulated plasma glucose and insulin levels in ob/ob mice. Author(s): Steerenberg PA, Beekhof PK, Feskens EJ, Lips CJ, Hoppener JW, Beems RB. Source: Diabetes Nutr Metab. 2002 August; 15(4): 205-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416657&dopt=Abstract

•

Low serum concentrations of insulin-like growth factor-I in children with active Crohn disease: effect of enteral nutritional support and glutamine supplementation. Author(s): Akobeng AI, Clayton PE, Miller V, Hall CM, Thomas AG. Source: Scandinavian Journal of Gastroenterology. 2002 December; 37(12): 1422-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523592&dopt=Abstract

•

Low whole-body insulin sensitivity in patients with ischaemic heart disease is associated with impaired myocardial glucose uptake predictive of poor outcome after revascularisation. Author(s): Kofoed KF, Carstensen S, Hove JD, Freiberg J, Bangsgaard R, Holm S, Rabol A, Hesse B, Arendrup H, Kelbaek H. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2002 August; 29(8): 991-8. Epub 2002 April 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173011&dopt=Abstract

•

Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smokeexposed ferrets. Author(s): Liu C, Lian F, Smith DE, Russell RM, Wang XD. Source: Cancer Research. 2003 June 15; 63(12): 3138-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810641&dopt=Abstract

•

Malnutrition, zinc supplementation and catch-up growth: changes in insulin-like growth factor I, its binding proteins, bone formation and collagen turnover. Author(s): Doherty CP, Crofton PM, Sarkar MA, Shakur MS, Wade JC, Kelnar CJ, Elmlinger MW, Ranke MB, Cutting WA.

Alternative Medicine 183

Source: Clinical Endocrinology. 2002 September; 57(3): 391-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201833&dopt=Abstract •

Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Author(s): Vincent MA, Montagnani M, Quon MJ. Source: Curr Diab Rep. 2003 August; 3(4): 279-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866989&dopt=Abstract

•

Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Author(s): Patrick L. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2002 August; 7(4): 276-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197781&dopt=Abstract

•

Oral insulin supplementation attenuates atherosclerosis progression in apolipoprotein E-deficient mice. Author(s): Shamir R, Shehadeh N, Rosenblat M, Eshach-Adiv O, Coleman R, Kaplan M, Hamoud S, Lischinsky S, Hayek T. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 January 1; 23(1): 10410. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524232&dopt=Abstract

•

Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Author(s): Rodriguez-Moran M, Guerrero-Romero F. Source: Diabetes Care. 2003 April; 26(4): 1147-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12663588&dopt=Abstract

•

Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Author(s): Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ, Bell RA; The Insulin Resistance and Atherosclerosis Study (IRAS). Source: Diabetes Care. 2002 December; 25(12): 2172-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453956&dopt=Abstract

•

Polyunsaturated fatty acids reduce insulin and very low density lipoprotein levels in broiler chickens. Author(s): Crespo N, Esteve-Garcia E. Source: Poultry Science. 2003 July; 82(7): 1134-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872970&dopt=Abstract

184 Insulin

•

Potentiation of insulin signaling in tissues of Zucker obese rats after acute and longterm treatment with PPARgamma agonists. Author(s): Jiang G, Dallas-Yang Q, Li Z, Szalkowski D, Liu F, Shen X, Wu M, Zhou G, Doebber T, Berger J, Moller DE, Zhang BB. Source: Diabetes. 2002 August; 51(8): 2412-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145152&dopt=Abstract

•

Protection of insulin-secreting INS-1 cells against oxidative stress through adenoviral-mediated glutathione peroxidase overexpression. Author(s): Moriscot C, Richard MJ, Favrot MC, Benhamou PY. Source: Diabetes & Metabolism. 2003 April; 29(2 Pt 1): 145-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746635&dopt=Abstract

•

Pulp-capping with recombinant human insulin-like growth factor I (rhIGF-I) in rat molars. Author(s): Lovschall H, Fejerskov O, Flyvbjerg A. Source: Advances in Dental Research. 2001 August; 15: 108-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640754&dopt=Abstract

•

Reduction and prevention of the cardiovascular sequelae of the insulin resistance syndrome. Author(s): Russell JC. Source: Current Drug Targets. Cardiovascular & Haematological Disorders. 2001 December; 1(2): 107-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769660&dopt=Abstract

•

Relationship of difficult laryngoscopy to long-term non-insulin-dependent diabetes and hand abnormality detected using the 'prayer sign'. Author(s): Erden V, Basaranoglu G, Delatioglu H, Hamzaoglu NS. Source: British Journal of Anaesthesia. 2003 July; 91(1): 159-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821580&dopt=Abstract

•

Release of acetylcholine by Die-Huang-Wan to enhance insulin secretion for lowering plasma glucose in Wistar rats. Author(s): Liou SS, Liu IM, Hsu JH, Wu YC, Hsu SF, Chen JT. Source: Autonomic Neuroscience : Basic & Clinical. 2002 September 30; 100(1-2): 21-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422956&dopt=Abstract

•

Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Author(s): Hallsten K, Virtanen KA, Lonnqvist F, Sipila H, Oksanen A, Viljanen T, Ronnemaa T, Viikari J, Knuuti J, Nuutila P.

Alternative Medicine 185

Source: Diabetes. 2002 December; 51(12): 3479-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453903&dopt=Abstract •

Seasonal variation in insulin sensitivity in healthy elderly people. Author(s): Bunout D, Barrera G, de la Maza P, Gattas V, Hirsch S. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 April; 19(4): 310-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679163&dopt=Abstract

•

Soy isoflavones do not modulate circulating insulin-like growth factor concentrations in an older population in an intervention trial. Author(s): Adams KF, Newton KM, Chen C, Emerson SS, Potter JD, White E, Lampe JW. Source: The Journal of Nutrition. 2003 May; 133(5): 1316-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730416&dopt=Abstract

•

Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism. Author(s): Khalil DA, Lucas EA, Juma S, Smith BJ, Payton ME, Arjmandi BH. Source: The Journal of Nutrition. 2002 September; 132(9): 2605-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221217&dopt=Abstract

•

Structural differences between rye and wheat breads but not total fiber content may explain the lower postprandial insulin response to rye bread. Author(s): Juntunen KS, Laaksonen DE, Autio K, Niskanen LK, Holst JJ, Savolainen KE, Liukkonen KH, Poutanen KS, Mykkanen HM. Source: The American Journal of Clinical Nutrition. 2003 November; 78(5): 957-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594782&dopt=Abstract

•

Supplementation of L-arginine improves hypertension and lipid metabolism but not insulin resistance in diabetic rats. Author(s): Kawano T, Nomura M, Nisikado A, Nakaya Y, Ito S. Source: Life Sciences. 2003 October 24; 73(23): 3017-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519450&dopt=Abstract

•

Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance. Author(s): Riserus U, Basu S, Jovinge S, Fredrikson GN, Arnlov J, Vessby B. Source: Circulation. 2002 October 8; 106(15): 1925-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12370214&dopt=Abstract

•

Tea enhances insulin activity. Author(s): Anderson RA, Polansky MM.

186 Insulin

Source: Journal of Agricultural and Food Chemistry. 2002 November 20; 50(24): 7182-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428980&dopt=Abstract •

The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Author(s): Allen NE, Appleby PN, Davey GK, Kaaks R, Rinaldi S, Key TJ. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2002 November; 11(11): 1441-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433724&dopt=Abstract

•

The effect of diet on serum insulin-like growth-factor-I and its main binding proteins. Author(s): Allen NE, Appleby PN, Davey GK, Key TJ, Rinaldi S, Kaaks R. Source: Iarc Sci Publ. 2002; 156: 295-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484190&dopt=Abstract

•

The effects of fiber enrichment of pasta and fat content on gastric emptying, GLP-1, glucose, and insulin responses to a meal. Author(s): Frost GS, Brynes AE, Dhillo WS, Bloom SR, McBurney MI. Source: European Journal of Clinical Nutrition. 2003 February; 57(2): 293-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571662&dopt=Abstract

•

The influence of coumestrol, zearalenone, and genistein administration on insulin receptors and insulin secretion in ovariectomized rats. Author(s): Nogowski L, Nowak KW, Kaczmarek P, Mackowiak P. Source: Journal of Receptor and Signal Transduction Research. 2002 FebruaryNovember; 22(1-4): 449-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503633&dopt=Abstract

•

The influence of dietary fat on insulin resistance. Author(s): Lovejoy JC. Source: Curr Diab Rep. 2002 October; 2(5): 435-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643169&dopt=Abstract

•

Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. Author(s): Wang S, DeGroff VL, Clinton SK. Source: The Journal of Nutrition. 2003 July; 133(7): 2367-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840208&dopt=Abstract

Alternative Medicine 187

•

Transfection of pancreatic-derived beta-cells with a minigene encoding for human glucagon-like peptide-1 regulates glucose-dependent insulin synthesis and secretion. Author(s): Hui H, Yu R, Bousquet C, Perfetti R. Source: Endocrinology. 2002 September; 143(9): 3529-39. Erratum In: Endocrinology 2002 November; 143(11): 4349. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193567&dopt=Abstract

•

Two herbal preparations, Cordyceps Cs4 and Cogent db: do they act on blood glucose, insulin sensitivity, and diabetes as “viscous dietary fibers?”. Author(s): Hockaday TD. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2002 August; 8(4): 403-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12230899&dopt=Abstract

•

Type of dietary fat and insulin resistance. Author(s): Rivellese AA, De Natale C, Lilli S. Source: Annals of the New York Academy of Sciences. 2002 June; 967: 329-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12079860&dopt=Abstract

•

Whole-grain intake and insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Author(s): Liese AD, Roach AK, Sparks KC, Marquart L, D'Agostino RB Jr, Mayer-Davis EJ. Source: The American Journal of Clinical Nutrition. 2003 November; 78(5): 965-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594783&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•

AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

•

Chinese Medicine: http://www.newcenturynutrition.com/

•

drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

•

Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

•

Google: http://directory.google.com/Top/Health/Alternative/

•

Healthnotes: http://www.healthnotes.com/

•

MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

•

Open Directory Project: http://dmoz.org/Health/Alternative/

188 Insulin

•

HealthGate: http://www.tnp.com/

•

WebMD®Health: http://my.webmd.com/drugs_and_herbs

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to insulin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com Colorectal Cancer Source: Integrative Medicine Communications; www.drkoop.com Depression Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Eating Disorders Source: Healthnotes, Inc.; www.healthnotes.com Fainting Source: Integrative Medicine Communications; www.drkoop.com Gestational Hypertension Source: Healthnotes, Inc.; www.healthnotes.com Gout Source: Healthnotes, Inc.; www.healthnotes.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com High Blood Pressure Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 189

High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Hirsuitism Source: Integrative Medicine Communications; www.drkoop.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hyperkalemia Source: Integrative Medicine Communications; www.drkoop.com Hypertension Source: Healthnotes, Inc.; www.healthnotes.com Hypertension Source: Integrative Medicine Communications; www.drkoop.com Hypertension Alternative names: High Blood Pressure Source: Prima Communications, Inc.www.personalhealthzone.com Hypoglycemia Source: Integrative Medicine Communications; www.drkoop.com Immune Function Source: Healthnotes, Inc.; www.healthnotes.com Insulin Resistance Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Low Blood Sugar Source: Integrative Medicine Communications; www.drkoop.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Obesity Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com

190 Insulin

Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Pancreatitis Source: Integrative Medicine Communications; www.drkoop.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com Prostate Cancer Source: Integrative Medicine Communications; www.drkoop.com Restless Legs Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Retinopathy Source: Healthnotes, Inc.; www.healthnotes.com Sleep Apnea Source: Integrative Medicine Communications; www.drkoop.com Syncope Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com Tinnitus Source: Healthnotes, Inc.; www.healthnotes.com •

Alternative Therapy Biofeedback Source: Integrative Medicine Communications; www.drkoop.com Biofeedback Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,675,00.html

•

Herbs and Supplements 5-htp Source: Integrative Medicine Communications; www.drkoop.com 5-hydroxytryptophan Source: Healthnotes, Inc.; www.healthnotes.com 5-hydroxytryptophan (5-htp) Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 191

Aesculus Alternative names: Horse Chestnut; Aesculus hippocastanum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Alfalfa Alternative names: Medicago sativa Source: Healthnotes, Inc.; www.healthnotes.com Aloe Alternative names: Aloe vera, Aloe barbadensis Source: Healthnotes, Inc.; www.healthnotes.com Alpha Lipoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Alpha2-adrenergic Agonists Source: Integrative Medicine Communications; www.drkoop.com Alpha-lipoic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10002,00.html American Ginseng Alternative names: Panax quinquefolium Source: Integrative Medicine Communications; www.drkoop.com Amino Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10003,00.html Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Amlodipine Source: Healthnotes, Inc.; www.healthnotes.com Arginine Source: Healthnotes, Inc.; www.healthnotes.com Arginine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10005,00.html Asian Ginseng Source: Healthnotes, Inc.; www.healthnotes.com

192 Insulin

Asian Ginseng Alternative names: Panax ginseng Source: Integrative Medicine Communications; www.drkoop.com Beta-blockers Source: Integrative Medicine Communications; www.drkoop.com Beta-glucan Source: Healthnotes, Inc.; www.healthnotes.com Bitter Melon Alternative names: Momordica charantia Source: Healthnotes, Inc.; www.healthnotes.com Bitter Melon Source: Prima Communications, Inc.www.personalhealthzone.com Bovine Colostrum Source: Healthnotes, Inc.; www.healthnotes.com Branched-chain Amino Acids Source: Healthnotes, Inc.; www.healthnotes.com Brewer’s Yeast Source: Healthnotes, Inc.; www.healthnotes.com Brewer's Yeast Alternative names: Nutritional Yeast Source: Integrative Medicine Communications; www.drkoop.com Cobalamin Source: Integrative Medicine Communications; www.drkoop.com Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q10 Source: Integrative Medicine Communications; www.drkoop.com Coenzyme Q10 (CoQ10) Source: Prima Communications, Inc.www.personalhealthzone.com CoQ10 Source: Integrative Medicine Communications; www.drkoop.com Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cynara C Alternative names: Cardoon; Cynara cardunculus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

Alternative Medicine 193

Dehydroepiandrosterone Source: Healthnotes, Inc.; www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com Diltiazem Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Eleuthero Alternative names: Siberian Ginseng, Eleuthero; Acanthopanax/Eleutherococcus senticosus Rupr. & Maxim. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Enalapril Source: Healthnotes, Inc.; www.healthnotes.com Eriodictyon Yerbasanta Alternative names: Yerba Santa; Eriodictyon californicum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Eugenia Clove Alternative names: Cloves; Eugenia sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Fenugreek Alternative names: Trigonella foenum-graecum Source: Healthnotes, Inc.; www.healthnotes.com Fenugreek Source: Prima Communications, Inc.www.personalhealthzone.com Fiber Source: Healthnotes, Inc.; www.healthnotes.com Fiber Source: Integrative Medicine Communications; www.drkoop.com Fibric Acid Derivatives Source: Integrative Medicine Communications; www.drkoop.com Fructo-Oligosaccharides (FOS) and Other Oligosaccharides Source: Healthnotes, Inc.; www.healthnotes.com Garcinia Cambogia Alternative names: Citrin, Gambooge Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

194 Insulin

Ginkgo Biloba Source: Healthnotes, Inc.; www.healthnotes.com Ginseng Source: Prima Communications, Inc.www.personalhealthzone.com Glimepiride Source: Healthnotes, Inc.; www.healthnotes.com Glipizide Source: Healthnotes, Inc.; www.healthnotes.com Glucomannan Source: Healthnotes, Inc.; www.healthnotes.com Glucosamine Source: Healthnotes, Inc.; www.healthnotes.com Glucosamine Source: Integrative Medicine Communications; www.drkoop.com Glucosamine Source: Prima Communications, Inc.www.personalhealthzone.com Glyburide Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza1 Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gurmar; Gymnema sylvestre Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gymnema sylvestre Source: Healthnotes, Inc.; www.healthnotes.com Gymnema Source: Prima Communications, Inc.www.personalhealthzone.com Gymnema Sylvestre Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10034,00.html Hibiscus Alternative names: Hibiscus, Roselle; Hibiscus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

Alternative Medicine 195

Horehound Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10036,00.html Humulus Alternative names: Hops; Humulus lupulus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Insulin Source: Healthnotes, Inc.; www.healthnotes.com Insulin Alternative names: Humalog, Humulin, Iletin, Novolin, Velosulin Source: Prima Communications, Inc.www.personalhealthzone.com Ipriflavone Source: Prima Communications, Inc.www.personalhealthzone.com Ispaghula Source: Integrative Medicine Communications; www.drkoop.com Kochia Alternative names: Summer Cypress, Fireweed; Kochia scoparia (L.) Schrad Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Lavandula Alternative names: Lavender; Lavandula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Lipase Source: Integrative Medicine Communications; www.drkoop.com Lipoic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Marshmallow Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10042,00.html Medium Chain Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Melatonin Source: Prima Communications, Inc.www.personalhealthzone.com Metformin Source: Healthnotes, Inc.; www.healthnotes.com

196 Insulin

Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com Mistletoe Alternative names: Viscum album Source: Healthnotes, Inc.; www.healthnotes.com Momordica Alternative names: Bitter Gourd, Karela; Momordica charantia Linn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org MSM Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,807,00.html Musa Banana Alternative names: Plantain, Banana; Musa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org N-acetyl-glucosamine Source: Healthnotes, Inc.; www.healthnotes.com Oral Hypoglycemics Source: Prima Communications, Inc.www.personalhealthzone.com Ornithine Source: Healthnotes, Inc.; www.healthnotes.com Ornithine Alpha-ketoglutarate Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Panax Ginseng Source: Integrative Medicine Communications; www.drkoop.com Panax Quinquefolium Source: Integrative Medicine Communications; www.drkoop.com Passiflora Alternative names: Passion Flower; Passiflora alata L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Phenothiazine Derivatives Source: Integrative Medicine Communications; www.drkoop.com Phosphorus Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 197

Phytolacca Alternative names: Poke root, Endod; Phytolacca dodecandra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Plantago Isphagula Source: Integrative Medicine Communications; www.drkoop.com Plantago Psyllium Alternative names: Psyllium, Ispaghula; Plantago psyllium/ovata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Psyllium Alternative names: Plantago ovata, Plantago ispaghula Source: Healthnotes, Inc.; www.healthnotes.com Psyllium Alternative names: Ispaghula,Plantago isphagula Source: Integrative Medicine Communications; www.drkoop.com Pyruvate Source: Healthnotes, Inc.; www.healthnotes.com Repaglinide Source: Healthnotes, Inc.; www.healthnotes.com Rosiglitazone Source: Healthnotes, Inc.; www.healthnotes.com Rosmarinus Alternative names: Rosemary; Rosmarinus officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Stevia Alternative names: Sweetleaf; Stevia rebaudiana Bertoni Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Sulfonylureas Source: Integrative Medicine Communications; www.drkoop.com Swertia Alternative names: Swertia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Syzygium Clove Alternative names: Clove, Jamun; Syzygium sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

198 Insulin

Taraxacum Alternative names: Dandelion; Taraxacum officinale (Dhudhal) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Taurine Source: Healthnotes, Inc.; www.healthnotes.com Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Thiazide Diuretics Source: Integrative Medicine Communications; www.drkoop.com Thioxanthene Derivatives Source: Integrative Medicine Communications; www.drkoop.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com Trace Minerals Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10061,00.html Tricyclic Antidepressants (TCAS) Source: Integrative Medicine Communications; www.drkoop.com Trigonella Alternative names: Fenugreek; Trigonella foenum graecum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vanadate Source: Integrative Medicine Communications; www.drkoop.com Vanadyl Source: Integrative Medicine Communications; www.drkoop.com Vasodilators Source: Integrative Medicine Communications; www.drkoop.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

199

CHAPTER 4. DISSERTATIONS ON INSULIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to insulin. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “insulin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on insulin, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Insulin ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to insulin. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

24-hour Ambulatory Blood Pressure: Relation to the Insulin Resistance Syndrome and Cardiovascular Disease by Bjorklund, Kristina; PhD from Uppsala Universitet (Sweden), 2002, 62 pages http://wwwlib.umi.com/dissertations/fullcit/f807569

•

A Comparison of Intensity of Educational Intervention on Knowledge, Attitude, Weight and Metabolic Control in Obese Individuals with Type Ii Non-insulin Dependent Diabetes Mellitus by D'eramo, Gail Ann, EDD from Columbia University Teachers College, 1987, 157 pages http://wwwlib.umi.com/dissertations/fullcit/8804209

•

A Role for Proteolysis of Insulin-like Growth Factor Binding Proteins in Ovarian Follicular Selection and Dominance by Rivera, Gonzalo Martin; PhD from Cornell University, 2002, 186 pages http://wwwlib.umi.com/dissertations/fullcit/3059149

200 Insulin

•

A Study of the Effect of an Anti-proliferative Agent on Rat Glial Tumor Cells: Effects on Insulin-like Growth Factor-1 Gene Expression and Action by Chacko, Sapna Mani; PhD from The University of Texas Health Science Center at San Antonio, 2002, 200 pages http://wwwlib.umi.com/dissertations/fullcit/3037924

•

Acute Effects of a Single Bout of Resistance Exercise on Insulin Sensitivity in Persons with Type-1 Diabetes Mellitus by Jimenez, Carolyn C.; PhD from Temple University, 2002, 181 pages http://wwwlib.umi.com/dissertations/fullcit/3040324

•

An Exploratory Study of the Organization of Family Roles and Responsibilities around the Presence of Insulin-dependent Diabetes in a Child (diabetes Mellitus, Childhood Diabetes) by Diulio, Rosemary J., EDD from Columbia University Teachers College, 1990, 159 pages http://wwwlib.umi.com/dissertations/fullcit/9113464

•

An Investigation of a Predictive Model of Self-management and Quality of Life in Adults with Non-insulin-dependent Diabetes Mellitus by Sabik, Sharon Frances; PhD from University of Arkansas, 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3067058

•

An Nmr Relaxation Study of Water Dynamics in Hydrated Insulin by Kakule, John Fred; PhD from The University of New Brunswick (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL43719

•

Antigenicity of Insulin by Mark, Yan-chu; Advdeg from McGill University (Canada), 1968 http://wwwlib.umi.com/dissertations/fullcit/NK02858

•

Binding of Epidermal Growth Factor and Insulin in Cells of Bone and Tooth As Revealed by Radioautography by Martineau-doizé Béatrice; PhD from McGill University (Canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL38387

•

Biologically Relevent Physical Studies of Insulin-enhancing Vanadium Complexes by Liboiron, Barry Dean; PhD from The University of British Columbia (Canada), 2002, 197 pages http://wwwlib.umi.com/dissertations/fullcit/NQ75040

•

Biotransport and Biocompatibility of Nanoporous Biocapsules for Insulinoma Cell Encapsulation by Leoni, Lara; PhD from University of Illinois at Chicago, 2003, 232 pages http://wwwlib.umi.com/dissertations/fullcit/3083871

•

Caffeine Ingestion Causes a Greater Insulin Response to an Oral Glucose Tolerance Test in Obese and Lean Males by Chown, Sara E.; MSC from University of Guelph (Canada), 2002, 91 pages http://wwwlib.umi.com/dissertations/fullcit/MQ65917

•

Caffeine Ingestion Increases the Insulin Response to an Ogtt in Obese, Resting Males before and after a Weight-loss Program by Petrie, Heather Jean; MSC from University of Guelph (Canada), 2002, 98 pages http://wwwlib.umi.com/dissertations/fullcit/MQ67370

Dissertations 201

•

Carbohydrate Recognition by the Insulin-like Growth Factor Ii/mannose 6-phosphate Receptor by Hancock, Michael Kenneth; PhD from The Medical College of Wisconsin, 2002, 217 pages http://wwwlib.umi.com/dissertations/fullcit/3090052

•

Central Leptin Administration Increases Insulin Sensitivity, Independent of Food Intake, and Sympathetic Activity in Diabetic Rats by Lin, Chia-yu; PhD from Auburn University, 2002, 143 pages http://wwwlib.umi.com/dissertations/fullcit/3044011

•

Characterization of Insulin Receptor Signaling Pathways That Mediate Potentiation of Nmda Receptor Activity by Skifter, Donald Albert; PhD from University of Nebraska Medical Center, 2002, 179 pages http://wwwlib.umi.com/dissertations/fullcit/3033994

•

Characterization of Non-insulin-dependent Diabetes Mellitus in an Amerindian Population: the New World Syndrome among the Mvskoke (non Insulin Dependent) by Valdez, Rodolfo Antonio, PhD from The Pennsylvania State University, 1991, 215 pages http://wwwlib.umi.com/dissertations/fullcit/9127439

•

Characterization of Pten, Tsc1, and Tsc2: Negative Regulators of the Insulin Signaling Pathway by Potter, Christopher John; PhD from Yale University, 2002, 258 pages http://wwwlib.umi.com/dissertations/fullcit/3046212

•

Cloning and Characterization of the Insulin Receptor-related Receptor (irr) Reveals That It Is Closely Associated Withtrka in the Genome and Maps to Human Chromosome 1q22, a Type 2 Diabetes Susceptibility Locus by Rainey, Susan Patricia; PhD from University of Toronto (Canada), 2002, 192 pages http://wwwlib.umi.com/dissertations/fullcit/NQ74768

•

Comparison of Strategies for Engineering Resistance to Damage Caused by Cytokines and Reactive Oxygen/nitrogen Species in Insulin Secreting Cell Lines by Tran, Veronique Vien; PhD from The University of Texas Southwestern Medical Center at Dallas, 2002 http://wwwlib.umi.com/dissertations/fullcit/f483345

•

Compartmentalized Insulin Signalling in 3t3-l1 Cells by Sampsel, Kari Lynn; Msc from University of Calgary (Canada), 2002, 139 pages http://wwwlib.umi.com/dissertations/fullcit/MQ72186

•

Conjugated Linoleic Acid and the Metabolic Syndrome. Clinical and Metabolic Studies with Special Reference to Insulin Resistance, Oxidative Stress and Inflammation by Riserus, Ulf Magnus; PhD from Uppsala Universitet (Sweden), 2002, 66 pages http://wwwlib.umi.com/dissertations/fullcit/f821473

•

Control of Lipid Homeostasis by the Combined Action of Two Insig Proteins: One Regulated by Srebps and the Other by Insulin by Yabe, Daisuke; PhD from The University of Texas Southwestern Medical Center at Dallas, 2003 http://wwwlib.umi.com/dissertations/fullcit/f38161

•

Correlates of Life-satisfaction among Long-term, Insulin Dependent Diabetics by White, Mitra Imani, PhD from The University of Utah, 1982, 101 pages http://wwwlib.umi.com/dissertations/fullcit/8220068

202 Insulin

•

Correlates of Neurocognitive Abilities in Adolescents with Insulin-dependent Diabetes Mellitus (IDDM) by Pollard, Naomi Lampert; PhD from The George Washington University, 2002, 119 pages http://wwwlib.umi.com/dissertations/fullcit/3045183

•

Delivery of Insulin-like Growth Factor I for Bone Repair by Meinel, Lorenz Werner; DRSCNAT from Eidgenoessische Technische Hochschule Zuerich (Switzerland), 2002, 116 pages http://wwwlib.umi.com/dissertations/fullcit/f833377

•

Detection of Hiss-dependent Insulin Action: Method Considerations by Reid, Maria April Genovey; Msc from The University of Manitoba (canada), 2002, 108 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76856

•

Determination and Characterization of the Functional Role of Nitric Oxide in the Regulation of Insulin Release by Smukler, Simon Ram; MSC from University of Toronto (Canada), 2002, 109 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74157

•

Development and Phenotypic Characterization of Transgenic Mice with Bonedirected Overexpression of Insulin-like Growth Factor-i by Jiang, Jin; PhD from The University of Connecticut, 2002, 148 pages http://wwwlib.umi.com/dissertations/fullcit/3046089

•

Dexamethasone Stimulation of Osteoprogenitor Differentiation in Adult Rat Bone Cell Populations Is Mediated in Part Through an Increased Response to Insulin-like Growth Factors by Jia, Dan; PhD from University of Toronto (Canada), 2003, 172 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78035

•

Dietary Fat Associated with Insulin Concentrations in Native American Adolescents by Cole, Suzanne Marilyn; PhD from The University of Arizona, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3053878

•

Disease Susceptibility in Human Insulin-dependent Diabetes Mellitus by Walsh, Linda Jane; PhD from Queen's University at Kingston (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK46411

•

Disordered Eating in Female Adolescents with Insulin Dependent Diabetes Mellitus by Schwartz, Stefanie Anrea; PhD from The Herman M. Finch U. of Health Sciences - the Chicago Medical Sch., 2002, 224 pages http://wwwlib.umi.com/dissertations/fullcit/3061543

•

Duration of Improved Muscle Insulin Action in the Obese Zucker Rat after a Single Exercise Session by Betts, Jeffrey John, PhD from The Ohio State University, 1990, 132 pages http://wwwlib.umi.com/dissertations/fullcit/9022476

•

Effect of Acute Isocaloric Exercise at Different Intensities on Glucose and Insulin Metabolism in Obese Individuals and Obese Patients with Non-insulin-dependent Diabetes Mellitus by Kang, Jie, PhD from University of Pittsburgh, 1994, 86 pages http://wwwlib.umi.com/dissertations/fullcit/9508282

•

Effect of Exercise on in Vivo Insulin Signaling and Action in Insulin Resistant Skeletal Muscle by Christ-roberts, Christine Yvonne; PhD from The University of Texas Health Science Center at San Antonio, 2003, 163 pages http://wwwlib.umi.com/dissertations/fullcit/3086768

Dissertations 203

•

Effects of Dietary Energy and Animal Frame Size on Feed Intake, Body Composition and Plasma Concentrations of Insulin and Leptin in Beef Steers by Ribeiro Filho, Claudio Crespo; PhD from Iowa State University, 2002, 122 pages http://wwwlib.umi.com/dissertations/fullcit/3073475

•

Effects of Hormone Replacement Therapy on Insulin Resistance in Cynomolgus Monkeys by Shadoan, Melanie Kimbrell; PhD from Wake Forest University, 2002, 134 pages http://wwwlib.umi.com/dissertations/fullcit/3082973

•

Effects of Hyperinsulinemia, Insulin Sensitivity, and Other Factors Associated with the Insulin Resistance Syndrome on Colorectal Epithelial Proliferation and Carcinogenesis in Rats by Tran, Thien Tram; PhD from University of Toronto (Canada), 2003, 238 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78428

•

Effects of Strength Training on Glucose and Insulin Response to an Oral Glucose Tolerance Test: Age and Gender Responses by Hurlbut, Diane Elizabeth; PhD from University of Maryland College Park, 2002, 217 pages http://wwwlib.umi.com/dissertations/fullcit/3055579

•

Effects of Zinc on the Insulin Receptor and Insulin Signal Transduction Pathway by Tang, Xiao-han; PhD from University of Illinois at Urbana-champaign, 2002, 119 pages http://wwwlib.umi.com/dissertations/fullcit/3044238

•

Endothelial Function, Insulin Action and Oxidative Stress in Vascular Disease: Studies on Pathogenesis and Prevention by Mcsorley, Paul Thomas; MD from Queen's University of Belfast (United Kingdom), 2002, 267 pages http://wwwlib.umi.com/dissertations/fullcit/f807985

•

Evaluation of an Andragogical Intervention on the Self-care Behaviors of Adults with Non-insulin Dependent Diabetes Mellitus by Robertson, Judith Lee; PhD from University of Arkansas, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3055343

•

Evaluation of Serum Insulin-like Growth Factor Binding Proteins and the Insulinlike Growth Factor Binding Protein-2 Locus for Potential Associations with Growth, Carcass Merit and Meat Quality in Beef Cattle by Pagan, Melvin; PhD from Michigan State University, 2002, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3053787

•

Evaluation of Serum, Urine, and Hair Chromium Levels As Indices of Chromium Exposure and the Relationship of These Indices to Serum Lipid and Insulin Levels by Randall, Janis Avril; PhD from University of Guelph (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL40576

•

Evaluation of the Acute Effects of Alpha-lipoic Acid and Fish Oil, Alone and in Combination, on the Postprandial Lipemic Response in Non-insulin-dependent Diabetes Mellitus by Kaye, Suzanne Avril; Msc from University of Guelph (Canada), 2002, 84 pages http://wwwlib.umi.com/dissertations/fullcit/MQ71198

•

Expression of Myostatin during Insulin-like Growth Factor-i-induced Myoblast Proliferation and Differentiation by Wong, Karen; MSC from University of Toronto (Canada), 2002, 130 pages http://wwwlib.umi.com/dissertations/fullcit/MQ73972

204 Insulin

•

Factors That Predict Self-care Behaviors of Non-insulin-dependent African Americans (diabetes Mellitus) by Campbell, Hal Lloyd, EDD from Northern Illinois University, 1993, 217 pages http://wwwlib.umi.com/dissertations/fullcit/9414226

•

Family Communication Patterns, Siblings, and Insulin-dependent Diabetic Children by Caldwell, Shirley Metz, EDD from Peabody College for Teachers of Vanderbilt University, 1983, 146 pages http://wwwlib.umi.com/dissertations/fullcit/8402951

•

Genetically Manipulated Mouse Models for the Study of Insulin-like Growth Factor I in Bone by Zhang, Mei; PhD from University of Cincinnati, 2002, 118 pages http://wwwlib.umi.com/dissertations/fullcit/3041148

•

Glucose- and Hypoxia-regulated Insulin Gene Expression by Tillmar, Linda Elisabet; PhD from Uppsala Universitet (Sweden), 2002, 62 pages http://wwwlib.umi.com/dissertations/fullcit/f383969

•

Glucose and Lipid Metabolism in Insulin Resistance: an Experimental Study in Fat Cells by Buren, Jonas; PhD from Umea Universitet (Sweden), 2002, 63 pages http://wwwlib.umi.com/dissertations/fullcit/f455681

•

Glucose Kinetics in Hormonal Disorders : the Role of Insulin by Elahi, Dariush; PhD from Dalhousie University (Canada), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK24922

•

Glut4 Activation: a Component of the Stimulation of Glucose Uptake by Insulin by Somwar, Rabindranauth-Romel; PhD from University of Toronto (Canada), 2002, 268 pages http://wwwlib.umi.com/dissertations/fullcit/NQ75588

•

Health Beliefs, Social Support, and Self-care Behaviors of Older Thai Persons with Non-insulin-dependent Diabetes Mellitus (NIDDM) by Surit, Pattama; DNSC from The Catholic University of America, 2002, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3047162

•

Hyperinsulinemia, Abnormal Glucose Tolerance and Subsequent Risk of Cancer by Saydah, Sharon Hope; PhD from The Johns Hopkins University, 2002, 128 pages http://wwwlib.umi.com/dissertations/fullcit/3046557

•

Identification and Characterization of Regulatory Mechanisms in the Insulin Receptor Signal Transduction Pathway by Wick, Michael Jude; PhD from The University of Texas Health Science Center at San Antonio, 2002, 165 pages http://wwwlib.umi.com/dissertations/fullcit/3061120

•

Identification of Genetic Factors Contributing to the Development of Type 1 (insulindependent) Diabetes Mellitus in the Northern Ireland Population by McCormack, Rose Margaret; PhD from Queen's University of Belfast (United Kingdom), 2002 http://wwwlib.umi.com/dissertations/fullcit/f402929

•

Identification of Serine Phosphorylation Sites in Insulin Receptor Substrate-1 That Inhibit Insulin Action by Aguirre, Vincent; PhD from Harvard University, 2002, 185 pages http://wwwlib.umi.com/dissertations/fullcit/3051101

•

In Vitro Expression of Human Insulin in Hep-3b, Hep-g2, and Hep-g2 (c3a) Cell Lines by Allen, Glenn Douglas; MSC from University of Calgary (Canada), 2002, 161 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76196

Dissertations 205

•

Insulin and Cyclical Obesity in the Dormouse, Glis Glis by Melnyk, Roman Bohdan; PhD from University of Toronto (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK50313

•

Insulin and Insulin-like Peptide Receptors of the Human Placenta Ontogeny and Regulation by Deal, Cheri; PhD from McGill University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK51924

•

Insulin Biosynthesis by the Pancreatic Islets of Langerhans Aspects of Regulation by Zucker, Peter F; PhD from University of Toronto (Canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK62245

•

Insulin Biosynthesis in Isolated Fetal Bovine B Cells by Rosenzweig, Steven Alan; PhD from University of Toronto (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK47149

•

Insulin Biosynthesis in the Brown Bullhead, Ictalurus Nebulosus by Moule, Margaret; PhD from University of Toronto (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK13795

•

Insulin Injection Site Selection and Cognitive Factors Associated with Diabetes Mellitus in Children by Rickabaugh, Timothy Elwood, PhD from Syracuse University, 1997, 156 pages http://wwwlib.umi.com/dissertations/fullcit/9842222

•

Insulin Regulation of Glucose Transport in Skeletal Muscle: Influence of Caffeine, Adenosine and Epinephrine by Thong, Farah Soke-ling; PhD from University of Guelph (Canada), 2002, 130 pages http://wwwlib.umi.com/dissertations/fullcit/NQ71753

•

Insulin Signaling Pathways and Glucose Transport: Role of Selenium As Insulin Mimetic. Mechanism of Induction of Insulin Resistance by Glucosamine by Heart, Emma; PhD from University of Southern California, 2002, 76 pages http://wwwlib.umi.com/dissertations/fullcit/3094331

•

Insulin Signalling and Regulation of Protein Kinase B in Adipocytes by Goransson, Olga Maria; PhD from Lunds Universitet (Sweden), 2003, 162 pages http://wwwlib.umi.com/dissertations/fullcit/f22353

•

Insulin-Dependent Diabetes Mellitus and Cognitive Dysfunction by Nash, Stacey S.; MA from Florida Atlantic University, 2002, 55 pages http://wwwlib.umi.com/dissertations/fullcit/1410397

•

Insulin-Like Growth Factor 1 Genotype, Phenotype and Breast Cancer Risk, by Racial/Ethnic Group by Delellis, Katherine Anne; MS from University of Southern California, 2002, 42 pages http://wwwlib.umi.com/dissertations/fullcit/1411781

•

Insulin-Like Growth Factor-I and Interleukin-6 Regulate Body Fat by Wallenius, Kristina; Meddr from Goteborgs Universitet (Sweden), 2002, 46 pages http://wwwlib.umi.com/dissertations/fullcit/f371521

•

Intracellular Signaling of Insulin-like Growth Factor Receptors in Neuronal Cells: Activation and Regulation of Akt Kinase Pathway and the Forkhead Family Transcription Factor Fkhrl1, and Their Role in Cell Survival by Zheng, Wenhua; PhD from McGill University (Canada), 2002, 381 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78805

206 Insulin

•

Investigation into the Mechanisms of Time-dependent Potentiation of Insulin Release in Rat Pancreatic Islets by Gunawardana, Subhadra Chandanie; PhD from Cornell University, 2002, 216 pages http://wwwlib.umi.com/dissertations/fullcit/3037241

•

Investigation of Biochemical Mechanisms Associated with Insulin Resistance in the Non-insulin-dependent Diabetes Mellitus by Huang, To-yu; PhD from The University of Tennessee, 2002, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3062309

•

Is Maternal Variability in the Insulin-like Growth Factor I Pathway Associated with Testicular Cancer Risk? A Case-parent Triad Study by Starr, Jacqueline Rose; PhD from University of Washington, 2003 http://wwwlib.umi.com/dissertations/fullcit/f204385

•

Islet Insulin Secretory Patterns in Diabetes and the Role of Ucp2 by Lin, Jian-man; PhD from Uppsala Universitet (Sweden), 2002, 37 pages http://wwwlib.umi.com/dissertations/fullcit/f383953

•

Kindergarten Intervention in Beginning Reading: Inoculation or Insulin? by Coyne, Michael Dennis; PhD from University of Oregon, 2001, 194 pages http://wwwlib.umi.com/dissertations/fullcit/3024511

•

Leptin and Insulin-like Growth Factor-i As Metabolic Indicators of Reproductive Performance in Brahman and Brahman-influenced Cattle by Strauch, Trista Ann; PhD from Texas A&M University, 2002, 112 pages http://wwwlib.umi.com/dissertations/fullcit/3072541

•

Loss of Function Analyses to Define a Role for Akt in Insulin Action by Cho, Han Joo; PhD from University of Pennsylvania, 2002, 225 pages http://wwwlib.umi.com/dissertations/fullcit/3043859

•

Loss of Insulin-like Growth Factor Ii Receptor in Tumorigenic Murine Cells: Effects on Growth and Invasion by Osipo, Clodia; PhD from Loyola University of Chicago, 2002, 128 pages http://wwwlib.umi.com/dissertations/fullcit/3039296

•

Mechanisms Involved in the Repression of Human Insulin Gene Promoter Activity Mediated by Chronic Hyperglycemia by Pino, Maria Fernanda; PhD from Michigan State University, 2002, 181 pages http://wwwlib.umi.com/dissertations/fullcit/3075063

•

Mechanisms of Insulin-regulated Trafficking by Lampson, Michael A.; PhD from Cornell University Medical College, 2002, 178 pages http://wwwlib.umi.com/dissertations/fullcit/3057637

•

Mechanisms of Somatostatin-induced Paradoxical Increase in Insulin Secretion in the Presence of Arginine Vasopressin in Clonal Beta-cell Hit-t15 by Cheng, Henrique; PhD from Iowa State University, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3051452

•

Metformin As an Adjunct to Insulin Therapy in Adolescents with Type 1 Diabetes: a Pilot Study by Hamilton, Jill Krysti; MSC from University of Toronto (Canada), 2002, 90 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68793

Dissertations 207

•

Modulation of Adipocyte Membrane Composition and Insulin Action in Normal and Diabetic States by Dietary Fat by Field, Catherine Jane; PhD from University of Alberta (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL45681

•

Modulation of Insulinotropic Hormone Bioactivity with a Focus on Glucosedependent Insulinotropic Polypeptide (GIP) and Its Receptor by Hinke, Simon Amadeus; PhD from The University of British Columbia (Canada), 2003, 244 pages http://wwwlib.umi.com/dissertations/fullcit/NQ79223

•

Non-insulin Dependent (Type II) Diabetes Mellitus in the Eastern Cherokee of Western North Carolina (Native American) by Quiggins, Patricia Ann, PhD from The University of Tennessee, 1990, 113 pages http://wwwlib.umi.com/dissertations/fullcit/9112876

•

Novel Signaling Pathways Involved in the Insulin Receptor Activation of Stat5 by Le, Maithao Ngoc; PhD from Mount Sinai School of Medicine of New York University, 2002, 125 pages http://wwwlib.umi.com/dissertations/fullcit/3054073

•

Ontogeny of the Somatotropin/insulin-like Growth Factor Axis in Beef Calves by Weston, Ashley Rebecca Schafer; MS from Mississippi State University, 2002, 44 pages http://wwwlib.umi.com/dissertations/fullcit/1410612

•

Perceptions and Coping Strategies of Parents of Preschool Children with Insulindependent Diabetes Mellitus by Feldman, Hilary Lee, PhD from University of Pittsburgh, 1993, 147 pages http://wwwlib.umi.com/dissertations/fullcit/9421463

•

Phosphatidylinositol-5-phosphate 4-kinase Beta Modulates Insulin Sensitivity by Lamia, Katja Antionette; PhD from Harvard University, 2003, 166 pages http://wwwlib.umi.com/dissertations/fullcit/3091605

•

Physical Activity, Hormone Replacement Therapy, and Insulin-resistant Coronary Artery Disease Risk Factors in Postmenopausal Women by Manns, Patricia Janine; PhD from Oregon State University, 2002, 99 pages http://wwwlib.umi.com/dissertations/fullcit/3044340

•

Physical and Biological Properties of Guinea Pig Insulin by Zimmerman, Arthur Eric; PhD from University of Toronto (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK25520

•

Physiological and Psychological Variables Contributing to Sexual Dysfunction in Female Insulin Dependent Diabetic Patients by Rice, Linda Diane, PhD from Loyola University of Chicago, 1987, 128 pages http://wwwlib.umi.com/dissertations/fullcit/8718293

•

Plasminogen Activator Inhibitor-1 and the Insulin Resistance Syndrome by Byberg, Liisa; PhD from Uppsala Universitet (Sweden), 2002, 57 pages http://wwwlib.umi.com/dissertations/fullcit/f840449

•

Polytherapeutic Approaches to the Control of Hyperglycemia in Non-insulin Dependent Diabetics in Korea by Gang, G-hyon, PhD from University of Florida, 1995, 267 pages http://wwwlib.umi.com/dissertations/fullcit/9607370

208 Insulin

•

Potential Roles for the Insulin-like Growth Factor Binding Proteins during Development of the Mouse Mammary Gland by Allar, Michael Anthony; PhD from The Pennsylvania State University, 2002, 195 pages http://wwwlib.umi.com/dissertations/fullcit/3064873

•

Prevention of Non-insulin-dependent Diabetes Mellitus (niddm) among the Southern Cheyenne: an Analysis of Its Prevalence, Risk Factors and Initial Treatment among Full-blood Indians by Lohn, Christina, PhD from University of Kansas, 1995, 199 pages http://wwwlib.umi.com/dissertations/fullcit/9627489

•

Proinsulin and Insulin Sensitivity As Predictors for Type 2 Diabetes Mellitus and Coronary Heart Disease: Clinical Epidemiological Studies with Up to 27 Years of Follow-up by Zethelius, Bjorn; MD from Uppsala Universitet (Sweden), 2003, 67 pages http://wwwlib.umi.com/dissertations/fullcit/f205857

•

Proinsulin C-peptide Deficiency Partially Accounts for the Differences in Peripheral Nerve Regeneration between Type 1 and Type 2 Diabetic Polyneuropathies by Pierson, Christopher Ronald; PhD from Wayne State University, 2002, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3071821

•

Proximal Insulin Receptor Signaling: Insulin Receptor Substrates and Glycogen Synthase Kinase 3 by Choi, Woo Sung; PhD from University of Southern California, 2002, 178 pages http://wwwlib.umi.com/dissertations/fullcit/3093747

•

Regional Oxygenation in Cardiac Surgery: Influence of Temperature, Pump Flow and Insulin by Lindholm, Lena Elisabeth; PhD from Goteborgs Universitet (Sweden), 2002, 49 pages http://wwwlib.umi.com/dissertations/fullcit/f807889

•

Regulation of Cell Motility and Actin Polymerization in Neuroblastoma Cells by Insulin-like Growth Factor I by Meyer, Gary Edward; PhD from University of Michigan, 2003, 144 pages http://wwwlib.umi.com/dissertations/fullcit/3079503

•

Regulation of Glucose Transporter Glut4 by Insulin by Murata, Haruhiko; PhD from Washington University, 2003, 168 pages http://wwwlib.umi.com/dissertations/fullcit/3095544

•

Regulation of Glucose-dependent Insulinotropic Polypeptide (gip) Receptor Expression in the Pancreatic Beta-cell by Lynn, Francis Christopher; PhD from The University of British Columbia (Canada), 2003, 209 pages http://wwwlib.umi.com/dissertations/fullcit/NQ79238

•

Regulation of Oscillatory Insulin Secretion by Phosphofructokinase (m-isoform) and Fatty Acids by La Ronde-richard, Ann-Marie Theresa; PhD from Boston University, 2003, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3084837

•

Regulatory Effects of Leptin on Insulin Secretion Target Phospholipase C-protein Kinase C, but Not Protein Kinase A, Signal Transduction in Islets from Neonatal Mice by Lee, Joo-won; PhD from Michigan State University, 2002, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3053769

Dissertations 209

•

Regulatory Role of Serotonin during the First Phase of Insulin Release : a Morphological and Functional Study by Bold, Mercedes L. De; PhD from Queen's University at Kingston (Canada), 1975 http://wwwlib.umi.com/dissertations/fullcit/NK24800

•

Representing Risk: an Actor-network Analysis of the Recombinant Dna Debate and the Dispute over Human Insulin Production in Germany by Robins, Rosemary Anne, PhD from University of New South Wales (australia), 1997 http://wwwlib.umi.com/dissertations/fullcit/f1819922

•

Risk Factors for Loss of Genomic Imprinting of Insulin Growth Factor Ii Gene in Normal Colonic Tissue and Blood by Cruz-correa, Marcia Roxana; PhD from The Johns Hopkins University, 2003, 158 pages http://wwwlib.umi.com/dissertations/fullcit/3080646

•

Role of Insulin in the Abnormal Glucagon Secretory Response to Hypoglycemia in Type 1 Diabetes by Zhu, Ying Y.; MS from Southern Connecticut State University, 2002, 24 pages http://wwwlib.umi.com/dissertations/fullcit/1407776

•

Role of Protein Tyrosine Phosphatase-pest in Nitric Oxide-induced Inhibition of Basal and Insulin-stimulated Cell Motility by Lin, Yi; PhD from The University of Tennessee Center for the Health Sciences, 2003, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3085400

•

Selection and Maintenance of a Qa-1-restricted T Cell with Specificity for Insulin by Sullivan, Barbara Anne; PhD from Emory University, 2003, 120 pages http://wwwlib.umi.com/dissertations/fullcit/3080366

•

Self-efficacy and Stage of Change As Predictors of Self-care Behaviors in Children with Insulin-dependent Diabetes Mellitus by Cant, M. E. Catherine; PhD from The George Washington University, 2003, 116 pages http://wwwlib.umi.com/dissertations/fullcit/3075179

•

Sociocultural Risk Factors of Non-insulin Dependent Diabetes Mellitus among Middle-class African Americans in Central Ohio by Robinson, Jacquelyn Patricia Price; PhD from The Ohio State University, 2003, 233 pages http://wwwlib.umi.com/dissertations/fullcit/3088884

•

Some Effects of Insulin and Growth Hormone on the Metabolism of Glucose and Fatty Acids by Cheng, Jose Sanidad; PhD from McGill University (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK15811

•

Southern Blot Analysis in the Hominoidea of the Insulin Gene and the Dna Region of Tandem Repeats 5' to the Insulin Gene in Humans by Neiswanger, Katherine, PhD from University of California, Los Angeles, 1985, 150 pages http://wwwlib.umi.com/dissertations/fullcit/8601908

•

Structural Studies of Insulin Receptor Activation and Recruitment of Ptp1b by Li, Shiqing; PhD from New York University, 2003, 127 pages http://wwwlib.umi.com/dissertations/fullcit/3089408

•

Structure and Autoregulation of the Insulin-like Growth Factor-1 Receptor Kinase by Favelyukis, Svetlana; PhD from State University of New York at Stony Brook, 2002, 155 pages http://wwwlib.umi.com/dissertations/fullcit/3092623

210 Insulin

•

Structure-function Relationships in Insulin and Glucagon by Hefford, Mary Alice; PhD from University of Ottawa (canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65691

•

Studies in Antibody Catalysis: I. Preparation and Evaluation of an Insulin Prodrug. Ii. Physiological Roles for the Antibody-catalyzed Oxidation of Water by Mcdunn, Jonathan Edward; PhD from The Scripps Research Institute, 2003, 148 pages http://wwwlib.umi.com/dissertations/fullcit/3083908

•

Studies on Insulin Secretion and Glucose Tolerance in Experimental Obesity and Diabetes by Dalpe-Scott, Marthe; PhD from University of Ottawa (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK65707

•

Studies on the Biosynthesis of Proinsulin and Insulin by Tung, Anthony Kai-cheong; Advdeg from University of Toronto (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK08821

•

Studies on the Pathway and Significance of the Receptor Mediated Internalization of Insulin and Epidermal Growth Factor in Rat Liver Parenchyma by Kay, Denis G; PhD from Mcgill University (Canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL44353

•

Studies on the Role of Insulin-like Growth Factor-i in Growth and Lactation by Kerr, David Ernest; PhD from The University of Saskatchewan (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL49917

•

Studies with a Computer-controlled Insulin Infusion System by Botz, Charles K; PhD from University of Toronto (Canada), 1976 http://wwwlib.umi.com/dissertations/fullcit/NK38681

•

The Association between Adult Literacy and Patient Education Factors of Non-insulin Dependent Diabetic Patients at Risk for Lower Extremity Amputation by Emery, Alfred Wyatt, Jr., PhD from The Ohio State University, 1991, 170 pages http://wwwlib.umi.com/dissertations/fullcit/9120655

•

The Biocultural Context of Low-income Mexican-american Women with Type Ii Noninsulin Dependent Diabetes and Its Implications for Health Care Delivery by Swinney, Gloria Luyas, PhD from The University of Texas at Austin, 1988, 277 pages http://wwwlib.umi.com/dissertations/fullcit/8816582

•

The Effect of a Psychosocial Support Group on Adaptations and Coping Strategies of Women with Insulin-dependent Diabetes Mellitus by Holvey, Erin Lyn, PhD from University of Southern California, 1989 http://wwwlib.umi.com/dissertations/fullcit/f3124324

•

The Effect of Family Responsibility Patterns on Diabetes Control in Children and Adolescents with Insulin-dependent Diabetes Mellitus by Vella, Anne Maxwell Mostellar, EDD from Auburn University, 1996, 104 pages http://wwwlib.umi.com/dissertations/fullcit/9619214

•

The Effect of Hiv Protease Inhibitors on Insulin Binding, Triglyceride Synthesis, Lipolysis, and Insulin Signaling in 3t3-l1 Adipocytes (immune Deficiency) by Cammalleri, Caterina; MSC from Concordia University (Canada), 2002, 132 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68404

•

The Effect of Infusing Epinephrine on Liver and Muscle Glycogenolysis during Exercise in Rats (adreno Demedullation, Catecholamines, Glucagon, Insulin, Glucose) by Arnall, David Alan, PhD from Brigham Young University, 1985, 130 pages http://wwwlib.umi.com/dissertations/fullcit/8601877

Dissertations 211

•

The Effect of Insulin on Glucose Metabolism in Muscle by Beitner, Rivka; AdvDeg from McGill University (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06360

•

The Effect of Insulin on the Transfer Rates of Glucose and Free Fatty Acid in Diabetes by Csorba, T. R; AdvDeg from McGill University (Canada), 1965 http://wwwlib.umi.com/dissertations/fullcit/NK00439

•

The Effect of Insulin, Blood Glucose Levels and Diazepam Following Transient Forebrain Ischemia in the Rat by Voll, Christopher Laurence; PhD from University of Calgary (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL54346

•

The Effect of Menstrual Cycle on Fasting Blood Glucose Patterns of Insulin Dependent Women with Diabetes Mellitus by Kandt, Denise Charmane, EDD from University of Arkansas, 1992, 159 pages http://wwwlib.umi.com/dissertations/fullcit/9334094

•

The Effect of N-acetylcysteine on Three in Vivo Models of Insulin Resistance by Haber, Christopher Andrew; MSC from University of Toronto (Canada), 2002, 158 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74149

•

The Effects of a Physical Activity Program on Children Ages 5 to 11 Years with Insulin-dependent Diabetes Mellitus by Campaigne, Barbara Naomi, PhD from The University of Michigan, 1982, 165 pages http://wwwlib.umi.com/dissertations/fullcit/8304458

•

The Effects of Exercise Training on Insulin Sensitivity and Glucose Tolerance: a Meta-analysis by Matson, Lawrence Gerald, EDD from University of Northern Colorado, 1994, 297 pages http://wwwlib.umi.com/dissertations/fullcit/9427454

•

The Effects of Insulin Action on Gluconeogenesis and Glycogenolysis in Vivo by Edgerton, Dale Scott; PhD from Vanderbilt University, 2002, 205 pages http://wwwlib.umi.com/dissertations/fullcit/3047433

•

The Effects of Nonsuppressible Insulin-like Protein on Bone Metabolism. by Bennett, Ann, PhD from The University of Texas at Austin, 1978, 109 pages http://wwwlib.umi.com/dissertations/fullcit/7900535

•

The Effects of Physical Activity on Insulin Binding to Monocytes by Vanhelder, Tomas; PhD from University of Toronto (Canada), 2003, 230 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78357

•

The Efficacy of Intensive Individual Play Therapy for Children Diagnosed with Insulin-dependent Diabetes Mellitus by Jones, Elizabeth Murphy; PhD from University of North Texas, 2000, 117 pages http://wwwlib.umi.com/dissertations/fullcit/9990800

•

The Insulin Secretory Response in Pancreatic Islets of Lean and Obese Mice by Black, Marsha A; PhD from University of Ottawa (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL53766

•

The Insulin-dependent Younger Diabetic Adult's Ways of Coping with Daily Stress and Its Relation to Perception of Condition Impact, Psychological Characteristics, and Adaptational Outcome Indicators by Jukelevics, Tibor, PhD from University of Southern California, 1989 http://wwwlib.umi.com/dissertations/fullcit/f3124340

212 Insulin

•

The Interaction of Family Characteristics and Metabolic Control in Type Ii Noninsulin-requiring Diabetes Mellitus (systems Theory) by Smith, Nancy M., PhD from The Florida State University, 1986, 208 pages http://wwwlib.umi.com/dissertations/fullcit/8616907

•

The Link between Insulin Resistance and Increased Vldl Secretion: Insights from the Apob/batless Mouse by Siri, Patty Wannarat; PhD from Columbia University, 2002, 184 pages http://wwwlib.umi.com/dissertations/fullcit/3066906

•

The Mechanisms Through Which Insulin and an Insulin-mimetic Regulate Food Intake and Body Weight by Air, Ellen Louise; PhD from University of Cincinnati, 2002, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3062415

•

The Oligomeric Structure and Subunit Composition of the Hepatic Insulin Receptor by Haynes, Frederick John; PhD from University of Toronto (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL31415

•

The Personal Meaning of Chronic Illness Within the Context of Everday Life: a Case Study of the Experiences of People with Insulin-dependent Diabetes (diabetes Mellitus) by Oram, Barbara Jean, PhD from University of Toronto (Canada), 1992, 225 pages http://wwwlib.umi.com/dissertations/fullcit/NN73787

•

The Relationship between Depression and Risk Factors for Insulin Resistance While Controlling for Stress and Social Support: Secondary Data Analysis of the Nhanes I by Gangwisch, James Edward; PhD from Columbia University, 2003, 277 pages http://wwwlib.umi.com/dissertations/fullcit/3088332

•

The Relationship between Diabetes Self-management and Executive Functions in Non-insulin-dependent Diabetes Mellitus by Merrick, Euriel Elsworth; PhD from Pacific Graduate School of Psychology, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3071917

•

The Relationship between Insulin Resistance Syndrome, Body Fat Distribution, Dietary Intake Variables and Subclinical Atherosclerosis in Obese Type 2 Diabetes by Hegazi, Refaat Mohamed; PhD from University of Pittsburgh, 2002, 179 pages http://wwwlib.umi.com/dissertations/fullcit/3054285

•

The Relationship of Obesity and Body Fat Distribution to Non-insulin Dependent Diabetes Mellitus in a Navajo Community by Hall, Teri-Christine Ruan, PhD from The University of Wisconsin - Madison, 1990, 92 pages http://wwwlib.umi.com/dissertations/fullcit/9027499

•

The Relationships among Knowledge of Diabetes, Attitude toward Diabetes, Family and Friends' Support, Benefits of and Barriers to Treatment and Compliance with Health Regimens of Jordanian Adolescents with Insulin Dependent Diabetes Mellitus by Al-akour, Nemeh Ahmad; DNSC from Widener University School of Nursing, 2003, 214 pages http://wwwlib.umi.com/dissertations/fullcit/3082998

•

The Role of Forebrain Glucoreceptors in the Counter-regulatory Response to Insulininduced Hypoglycemia by Cane, Patricia Irene, PhD from University of Southern California, 1985 http://wwwlib.umi.com/dissertations/fullcit/f1583877

Dissertations 213

•

The Role of Glucagon and Insulin in the Control of Glucose Turnover in Dogs by Cherrington, Alan D; PhD from University of Toronto (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK26047

•

The Role of Insulin Receptor Substrate-1 in Anaplastic Lymphoma Kinase Signaling by Kuo, Angera H.; PhD from Georgetown University Medical Center, 2003, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3085392

•

The Role of Insulin-like Growth Factor Binding Protein-related Protein-1 in Human Breast Cancer by Wilson, Heather-Marie Porterfield; PhD from University of Washington, 2002, 105 pages http://wwwlib.umi.com/dissertations/fullcit/3053574

•

The Role of Plc, Cpkc, L-type Calcium Channels and Camkii in Insulin-stimulated Glucose Transport in Skeletal Muscle by Wright, David Charles; PhD from Ball State University, 2002, 91 pages http://wwwlib.umi.com/dissertations/fullcit/3042285

•

The Role of Suppressor of Cytokine Signaling-3 in Interleukin-6 Dependent Insulin Resistance by Senn, Joseph James; PhD from The University of Rochester, 2003, 151 pages http://wwwlib.umi.com/dissertations/fullcit/3092243

•

The Role of the Hgrb14 Adaptor Protein Bps Domain in Insulin Signaling by Kelly, Sherrie Lynne; MSC from The University of Manitoba (canada), 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76780

•

The Short-term Efficacy of Bay G 5421 (acarbose) in Patients with Non-insulin Dependent Diabetes Mellitus by Silver, Dorothy Claire, EDD from Boston University, 1983, 112 pages http://wwwlib.umi.com/dissertations/fullcit/8401844

•

Transcriptional Regulation of Insulin-like Growth Factor-i by Interferon-gamma and Interleukin-4 in Macrophages by Wynes, Murry W.; PhD from University of Colorado Health Sciences Center, 2002, 205 pages http://wwwlib.umi.com/dissertations/fullcit/3056505

•

Variance Component Estimation for Reproductive Traits and Analyses of Myofibrillar Proteins and Age at Puberty in Angus Beef Cattle Divergently Selected for Blood Serum Insulin-like Growth Factor I Concentration by Yilmaz, Ahmet; PhD from The Ohio State University, 2003, 162 pages http://wwwlib.umi.com/dissertations/fullcit/3088898

•

Variation in the Gene for Insulin-like Growth Factor Ii and Its Relationship with Anthropometric Traits by Gaunt, Thomas Richard; PhD from University of Southampton (United Kingdom), 2002 http://wwwlib.umi.com/dissertations/fullcit/f403233

•

Vascular Growth after Balloon Catheter Injury in Normal Rats Treated with High-fat Diet and Insulin Implants by Kim, Tony Tae Yub; MSC from University of Toronto (Canada), 2002, 127 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68814

214 Insulin

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

215

CHAPTER 5. CLINICAL TRIALS AND INSULIN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning insulin.

Recent Trials on Insulin The following is a list of recent trials dedicated to insulin.8 Further information on a trial is available at the Web site indicated. •

A clinical trial to prevent the complications of insulin resistance (including type-2 diabetes) Condition(s): Insulin Resistance; Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: The goal of this study is to aggressively treat insulin resistance and its clinical manifestations when they first appear in childhood, and to prevent the subsequent progression towards impaired glucose tolerance and type-2 diabetes. In the process of this clinical trial, we will learn more about the early manifestations of insulin resistance, its treatment, and its relationship to obesity and type-2 diabetes through parallel in-vivo and in-vitro studies. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015626

•

Aging and Cellular Mechanism for Insulin Action after Exercise Training Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients.

8

These are listed at www.ClinicalTrials.gov.

216 Insulin

Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study will determine whether the metabolic and cellular mechanisms contributing to improved insulin action after aerobic or resistive exercise are different in older, obese, insulin resistant veterans. The hypothesis is that regular exercise, whether aerobic or resistive, will improve whole body insulin action, but the nature and magnitude of changes in skeletal muscle will differ between the two types of exercise. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018239 •

Bypass Angioplasty Revascularization Investigation in Type 2 Diabetics (BARI 2D) Condition(s): Coronary Disease; Cardiovascular Diseases; Heart Diseases; Insulin Resistance; Diabetes Mellitus; Diabetes Mellitus, non-insulin dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2800 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of <7.0% for all patients). SPECIFIC AIMS A. Primary Aim The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2800 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity: 1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone; 2. Method of Glycemic Control Hypothesis: with a target HbA1c level of <7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared to a strategy of insulin provision. B. Secondary Aims The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006305

Clinical Trials 217

•

Compare blood sugar level between Lantus in the morning and other insulins in Type 1 diabetes adolescents Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): Aventis Pharmaceuticals Purpose - Excerpt: The purpose of the study is to compare the effect in blood sugar control between Lantus and twice daily intermediate acting insulins (NPH or Lente) when used as the basal insulin in a multiple daily injection setting with fast acting insulin (Lispro) Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046501

•

Continuous Glucose Monitoring in Children With Type 1 Diabetes Mellitus Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will evaluate the safety and effectiveness of a continuous glucose monitor in children with Type 1 diabetes mellitus (T1DM). Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069628

•

Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People Condition(s): Obesity; Insulin Resistance Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: This study will examine whether glucosamine affects the way the body responds to insulin. Insulin is a hormone that causes the body to use glucose (sugar). Insulin does not work as well in overweight people, causing a condition called insulin resistance. Insulin also increases the flow of blood into muscle by opening inactive blood vessels. This study will test whether glucosamine, a nutritional supplement that many people take to treat arthritis, can cause or worsen insulin resistance or change how blood vessels react to insulin in normal weight and overweight people. Healthy normal weight and overweight volunteers between 21 and 65 years of age may be eligible for this study. Candidates will be screened with a brief physical examination, medical history, and blood and urine tests. After screening, participants will have three additional outpatient clinic visits for the following procedures: Visit 1 - Glucose clamp test to measure the body's response to insulin: For this procedure, a needle is placed in a vein of each arm, one for drawing blood samples,

218 Insulin

and one for infusing glucose and a potassium solution. The glucose is infused continuously during this 4-hour test and blood is drawn frequently to monitor glucose and insulin levels. After the test, blood glucose levels are monitored for another 2 hours to make sure they remain at an adequate level to prevent hypoglycemia (low blood sugar). - Blood flow measurement: Blood flow in the brachial artery of the arm is measured to assess how many capillaries (very small blood vessels) are being used to supply nutrients and oxygen to the muscle in the forearm. This test is done at the same time as the glucose clamp test. Blood flow is measured using a technique called contrast ultrasound. A small amount of contrast agent consisting of gas-filled bubbles the size of red blood cells is infused over 10 minutes through one of the catheters placed in the vein for the glucose clamp test. The contrast agent is infused twice, once at the beginning of the glucose clamp test and once at the end of the test. The contrast material creates a signal in response to ultrasound that provides information about the distribution of capillaries in the forearm. - Assignment to medication group: Participants are randomly assigned to take either glucosamine or placebo three times a day by mouth for 6 weeks. At the end of the 6 weeks, no study drug is taken for 1 week, and then participants "cross-over" medications, those who took glucosamine for the first 6 weeks take placebo for the next 6 weeks and vice versa. Visits 2 and 3 For these visits, the glucose clamp test and blood flow measurements are repeated. Visit 2 is scheduled at the end of the first 6week treatment period, and Visit 3 is scheduled at the end of the second 6-week treatment period. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065377 •

Evaluation of a Diabetes Vaccine in Newly Diagnosed Diabetics Condition(s): Insulin-Dependent Diabetes Mellitus; Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Immune Tolerance Network Purpose - Excerpt: Insulin dependent diabetes mellitus (also called type 1 diabetes mellitus or T1DM) is caused by the destruction of insulin-producing cells in the pancreas. People with T1DM do not produce enough insulin, which is necessary for proper regulation of blood sugar levels. T1DM is an autoimmune disease. An autoimmune disease is a disease in which the body's immune system attacks the body itself. In addition to regulating blood sugar, insulin may have the ability to protect cells in the pancreas from attack by the immune system. This study will evaluate whether an insulin-based vaccine can protect cells from autoimmune destruction. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057499

•

Genetic Studies of Insulin and Diabetes Condition(s): Diabetes Mellitus; Insulin Resistance

Clinical Trials 219

Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The study will allow researchers to obtain blood, plasma, DNA, and RNA for genetic studies of insulin. There will be a focus on the causes of insulin resistance and diabetes mellitus. Insulin is a hormone found in the body that controls the level of sugar in the blood. Insulin resistance refers to conditions like diabetes when insulin does not work properly. In this study researchers would like to compare patients with diabetes and other forms of insulin resistance to normal individuals. The study will investigate how insulin attaches to cells. Researchers will take 4 to 6 ounces (100-150 ml) of blood from adult patients and may request up to 12 ounces (one unit) of blood if necessary. Skin samples may be taken for a biopsy if further genetic testing is necessary. In addition some patients may be asked not to eat for up to 72 hours prior to testing. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001987 •

Genetic Study of Insulin-Like Growth Factor-I Receptor Mutations in Patients With Intrauterine Growth Retardation Condition(s): Intrauterine Growth Retardation Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Determine if mutations in the gene encoding the insulin-like growth factor-I receptor lead to relative insulin-like growth factor-I insensitivity and produce intrauterine growth retardation in children. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005105

•

Ginkgo Biloba Extract and the Insulin Resistance Syndrome Condition(s): Type 2 diabetes mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: The purpose of this study is to examine whether the ingestion of the herbal dietary supplement Ginkgo biloba extract has any effect on the efficacy of three classes of diabetic medications - (Glucotrol, Glucophage and Actose). Additionally, the study will examine the effect of Ginkgo biloba extract on pancreatic insulin production in non-diabetic subjects between the ages of 20 and 75 years old. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00032474

220 Insulin

•

hOKT3gamma1 (Ala-ala) for the prevention of human islet allograft failure Condition(s): Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Experimental; Transplantation, Homologous; Islets of Langerhans Transplantation Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Juvenile Diabetes Research Foundation; Juvenile Diabetes Foundation International Islet Transplantation Center Purpose - Excerpt: The broad, long-term goal of this proposal is to improve the results and applicability of islet allotransplantation early in the course of type 1 diabetes through the administration of selective and short-term immunotherapy. More specifically, the objectives of these studies is to conduct an open-labeled, one-year follow-up Phase I/II study in patients with surgican and type 1 diabetes to determine the safety, tolerability, immune activity, and pharmacokinetics of hOKT3gammal1 (Alaala) administration for the prevention of autoimmune destruction and rejection of allogeneic islet transplants. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00008801

•

Insulin Aspart vs. Insulin Lispro vs. Regular Insulin in Pediatric Population Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): Novo Nordisk Pharmaceuticals Purpose - Excerpt: Insulin Aspart vs. Insulin Lispro vs. Regular Insulin in Pediatric Population Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00071448

•

Insulin Resistance and Insulin Secretion Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This is a pilot study to examine the prevalence of metabolic risk factors (impaired insulin release and impaired insulin sensitivity) for type 2 diabetes mellitus in children and adults from a population that is at high risk for this disease. We hypothesize that at least one of these pre-diabetic traits will be evident in a large proportion of relatives of known type 2 diabetic children as compared to a control group of subjects without a family history of type 2 diabetes. By isolating these traits, it will be possible to determine the relative contributions of genes and environment to each trait and to identify those at risk for subsequent development of type 2 diabetes by virtue of having one trait. Ultimately, those individuals at risk, especially those with impaired insulin release, would hopefully benefit from intervention to prevent the weight gain

Clinical Trials 221

that will 'unmask' their underlying pancreatic dysfunction and thus prevent or retard the development of type 2 diabetes. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073294 •

Insulin, Neurogentics and Memory in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study examines the use of insulin-sensitizing compounds, as therapeutic agents for cognitive impairment in Alzheimer's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018382

•

Interferon-Alpha for Diabetes Mellitus Type 1 Condition(s): Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will examine whether interferon alpha can prevent or minimize the risk of complications from diabetes type 1. This type of diabetes results when the body's immune system attacks cells in the pancreas that produce insulin, a hormone that helps regulate blood sugar levels. Many common complications of diabetes, such as blindness, kidney failure, nerve damage and artery disease leading to heart attacks and strokes, are related to high blood sugar. This study will see if interferon alpha, given early in the disease, can stop or slow the immune attack on insulin-producing cells. Animal experiments have shown that interferon alpha taken by mouth may stop the development of diabetes. Patients between 3 and 25 years of age with type 1 diabetes mellitus of less than 6 weeks duration may be eligible for this study. Candidates undergo a medical history, physical examination, routine and research blood tests, a urine test and a Boost stimulation test. For the Boost test, patients fast overnight and do not take the next morning's insulin dose. A blood sample is drawn to measure fasting sugar and C-peptide levels. The patient then drinks a food supplement (Boost High Protein) and blood draws are repeated for sugar and C-peptide measurements at 15, 30, 60, 90 and 120 minutes after ingesting the liquid. Participants are randomly assigned to treatment with either interferon alpha or placebo (an inactive, look-alike substance) once a day by mouth for up to 12 months. The active compound consists of either 5,000 or 30,000 units of interferon alpha in a tablespoon of salt water; the placebo consists of salt water alone. Follow-up visits are scheduled at 1, 2, 3, 6, 9 and 12 months for a repeat Boost test, routine and research blood tests, and a physical examination to evaluate possible drug effects. A small blood sample will be drawn for HLA-typing, a genetic test similar to blood typing, to examine the makeup of genes thought to affect diabetes. The results of the genetic studies will be kept confidential.

222 Insulin

Patients who finish 12 months of treatment before the entire study ends may decide to continue treatment until all study patients completed the protocol. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024518 •

Laparoscopy to Remove Pancreatic Tumors (Insulinomas) Condition(s): Insulinoma Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will determine if laparoscopy can be used successfully to find and remove insulinomas (insulin-secreting tumors of the pancreas). These tumors are very small and often difficult to locate with magnetic resonance imaging (MRI), computed tomography (CT) or ultrasound. Invasive procedures, such as arteriograms (X-ray imaging using a contrast agent injected into the bloodstream through a catheter) and venous sampling are more successful but involve more patient discomfort and greater risk. This study will test whether laparoscopy can be used to replace some or all of these tests, as well as more extensive surgery. Patients 11 years of age and older with low blood sugar (hypoglycemia) probably caused by an insulinoma may be eligible for this study. Candidates will have their hypoglycemia confirmed (with tests done under NIH protocol 91-DK-0066: Diagnosis and Treatment of Hypoglycemia) and will have CT imaging of the abdomen and MRI and ultrasound tests of the liver and pancreas. Patients whose tumors are not found by these studies will undergo arteriography of the pancreas and hepatic (liver) venous sampling. Patients will then have laparoscopy. This surgical procedure uses a laparoscope-a tube-like device with special cameras and an ultrasound probe attached through which the surgeon can see and operate inside the abdomen. Laparoscopy is commonly done to remove the gallbladder and is also used to remove portions of the pancreas. For the current procedure, the surgeon makes small incisions in the abdomen, inserts tubes, fills the abdomen with gas, and proceeds to explore and operate on the pancreas. The surgeon will try to locate the tumor with the laparoscope. If the tumor is found, the location will be verified by the imaging study results. If it cannot be located by laparoscopy, the results of the imaging studies will be disclosed to enable removal. If the tumor cannot be successfully removed using the laparoscope, standard surgery will then be performed. If the tumor cannot be found though laparoscopy, imaging studies, or traditional surgery, the operation will be concluded without removing any of the pancreas. Medical treatment will be initiated and re-evaluation will be recommended after 6 months. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005910

•

LY333531 Treatment for Symptomatic Peripheral Neuropathy in Patients with Diabetes. Condition(s): Diabetic Neuropathies; Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Non-Insulin-Dependent

Clinical Trials 223

Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this protocol is to determine if an investigational drug known as LY333531 is effective in treating nerve malfunction in diabetes. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00044408 •

Metabolic Differences of Overweight Children and Children of Overweight Parents Condition(s): Cardiovascular Disease; Hypertension; Non Insulin Dependent Diabetes Mellitus; Obesity Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: This study focuses on the way weight is gained. Individuals who gain weight primarily in their midsection (visceral weight) are at an increased risk for developing diabetes and high blood pressure. Research has shown that African Americans suffer more often from high blood pressure, diabetes (non-insulin dependent), and heart disease than Caucasian Americans. These conditions lead to significant numbers of deaths and diseases associated with and made worse by obesity. African American women in particular suffer from obesity and the associated conditions of obesity more than any other race or gender. However, it is unknown if the conditions seen in African American women are a result of the obesity or differences in their insulin sensitivity, glucose disposal, or fat metabolism. This study will compare body composition, total and resting energy expenditure, and glucose disposal of obese African American and Caucasian children and of non-obese children of obese African American and Caucasian parents, to characterize the timing and nature of factors that may contribute to the prevalence of obesity and its complications. Patients participating in this study will be followed for 15 years and be evaluated every 5 years during the study. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001522

•

Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Patients with Insulin and Fat Abnormalities Condition(s): HIV Infections; Lipodystrophy; Hyperinsulinemia Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to see whether metformin alone, rosiglitazone alone, or metformin and rosiglitazone together will lower insulin levels in the blood and decrease fat in the abdomen or other parts of the body. Studies have shown that certain anti-HIV medications can cause a number of side effects, including high blood sugar (resulting from the body's failure to use insulin), high insulin, and excess fat build-up in the abdominal area. These side effects are known to increase the

224 Insulin

risk of heart disease. Metformin and rosiglitazone are 2 drugs that have been shown to lower insulin resistance and lessen abdominal fat in patients who are not HIV-infected. This study will investigate the use of these drugs in HIV-infected patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015691 •

Metformin to Treat Obesity in Children with Insulin Resistance Condition(s): Hyperinsulinemia; Obesity Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: This study will examine the safety and effectiveness of the medicine metformin to help overweight children control their food intake, weight, insulin, cholesterol, and triglyceride (blood fat) levels. Obesity and high insulin levels can lead to high blood pressure, diabetes, high cholesterol and triglyceride levels and heart disease. Metformin-approved by the Food and Drug Administration to treat adults with type 2 diabetes mellitus-helps lower insulin levels and may control weight gain in adults. Overweight children 6 to 11 years old who are in general good health may be eligible for this study. Children will be studied at the National Institutes of Health in Bethesda, Maryland, and at the Phoenix Indian Medical Center and the Gila River Reservation in the Phoenix, Arizona area. Candidates will have a medical history and physical examination and fasting blood test, and will provide a 7-day record of their food intake as part of the screening process. Those enrolled will be randomly assigned to receive either metformin or placebo (a look-alike tablet with no active medicine) twice a day for a six month period. After the 6 month study period, all children will be offered the opportunity to take metformin for another 6 months. Participants will be hospitalized for 2-3 days for the following procedures: history and physical examination; fasting blood test; several urine collections; X-ray studies to determine bone age and amount of body fat and muscle; magnetic resonance imaging (MRI) scan to measure body fat; "hyperglycemic clamp study" to evaluate insulin resistance; food intake testing; nutrition consultation; resting metabolic rate; and a "doubly labeled water" test. For the hyperglycemic clamp study, a catheter (thin flexible tube) is inserted into a vein in each arm. A sugar solution is given through one tube and blood samples are drawn every 5 minutes through the other to measure insulin. For the food intake testing, the child is asked about his or her hunger level, then given various foods he or she may choose to eat, then questioned again at various intervals both during and after finishing eating about his or her hunger level. The doubly labeled water study involves drinking "heavy water" (water which is enriched to have special kinds of hydrogen and oxygen). Urine specimens are collected 2, 3 and 4 hours after drinking the water. The child also drinks a special milk shake called a Scandishake and repeats the calorie intake and hunger study. (Two food intake studies are done on separate days.) One week after the heavy water test, additional urine samples are collected one week later. After completing the tests, the child will begin treatment with metformin or placebo, plus a daily vitamin tablet. Participants will be followed once a month with a brief history and physical examination, including a blood test. After 6 months, all of the tests described above will be repeated. All children who complete the second round of tests-both those who took metformin and those who took placebo-will be offered metformin for an additional 6 months and will be seen once a month for follow-up evaluations. Parents

Clinical Trials 225

will not be told which children received metformin and which received placebo until all children in the study complete the first 6 months of the trial. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005669 •

Methods for Measuring Insulin Sensitivity Condition(s): Obesity; Hypertension; Diabetes-Mellitus, Non-Insulin Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: Patients with high blood pressure, diabetes, and who are overweight are known to have defects in the way their body responds to insulin. The purpose of this study is to develop better methods for measuring the way body tissue responds to insulin and sugar (glucose). Researchers are planning to study four groups of patients. 1. Normal volunteers 2. Patients who have mild to moderate high blood pressure 3. Patients who are overweight 4. Patients who have mild to moderate diabetes controlled with oral medication In this study patients and volunteers will undergo two separate tests designed to determine how well insulin is working in the body. The first test is called a glucose clamp test. Patients will have two needles placed in the veins of their arms. One needle will be used to take blood samples, the other needle will be used to inject doses of sugar (glucose) and insulin. The second test is called the frequently sample intravenous glucose tolerance test. In this test patients will have sugar (glucose) injected into their veins followed by a slow injected dose (infusion) of insulin. Researchers will periodically take blood samples during the test. Patients participating in the study will not directly benefit from it. However, the information gained from this study may be useful for improving the diagnosis and therapy of diseases such as diabetes, obesity, and high blood pressure (hypertension). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001625

•

Safety & Efficacy of Insulin Aspart vs. Regular Human Insulin in Gestational Diabetes Condition(s): Gestational Diabetes Study Status: This study is currently recruiting patients. Sponsor(s): Novo Nordisk Pharmaceuticals Purpose - Excerpt: The purpose of this study is to test whether NovoLog (insulin aspart) is a safe and at least as effective alternative to regular human insulin for the control of blood glucose after meals in women who develop diabetes during pregnancy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065130

226 Insulin

•

Safety and Efficacy of Human Insulin Inhalation Powder in Patients with Type 1 Diabetes Mellitus. Condition(s): Diabetes Mellitus, Type 1 Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: This is a research study of a study drug known as LY041001 or human insulin inhalation powder (HIIP). HIIP is a powder form of insulin made to be inhaled through the mouth and into the lungs using a special handheld device. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063128

•

Safety and Efficacy of INGAP-Peptide in Patients with Type 1 Diabetes Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): Procter & Gamble Pharmaceuticals Purpose - Excerpt: Insulin is a chemical that the body needs in order to use or store sugar. It is made by a type of cell called a beta cell which resides in an organ known as the pancreas. Type 1 diabetes is a disease where the beta cells have been destroyed so that little or no insulin is made. Sugar levels rise in the blood as a result. INGAPPeptide is being tested to attempt to create new beta cells in the pancreas, and to restore the ability to produce insulin in type 1 diabetic patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00071409

•

Safety and Pharmacokinetics (PK) of hOKT3g1 (Ala-Ala) in Type 1 Diabetes Mellitus (T1DM) Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: To assess the tolerability and safety of hOKT3g1 (Ala-Ala) after a 12day dosing regimen administered via intravenous infusion. To assess the pharmacokinetics of hOKT3g1 (Ala-Ala). Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073255

Clinical Trials 227

•

Study Of Avandamet With Or Without Insulin In Type II Diabetes Mellitus Patients Condition(s): Non-Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: The purpose of this study is to test the safety and efficacy (how well it works) of Avandamet in combination with insulin in improving the control of blood sugar when compared with taking insulin on its own. Avandamet capsules contain a fixed dose of Avandia and metformin. Both Avandia and metformin are medicines which are individually licensed for the treatment of type II diabetes mellitus. Because they act in different ways, it is thought that combining them may give an increased benefit of treating diabetes and reducing blood sugar. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069836

•

Study of Recombinant Human Insulin-Like Growth Factor I in Patients with Severe Insulin Resistance Condition(s): Insulin Resistance; Hyperglycemia Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; Beth Israel Deaconess Medical Center Purpose - Excerpt: Objectives: I. Determine the efficacy and toxic effects of recombinant human insulin-like growth factor I (rhIGF-I) on carbohydrate tolerance, insulin action, insulin secretion, hyperandrogenism, and hyperlipidemia in patients with severe insulin resistance who have failed other therapies. II. Determine the dose and time response of rhIGF-I on carbohydrate homeostasis and secondary abnormalities in this patient population. III. Determine the effect of rhIGF-I on insulin clearance, the regulation of insulin-like growth factor binding protein 1, the regulation of sex hormone binding globulin, and hypothalamic pituitary gonadal axis in this patient population. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004419

•

Study Of Subjects With Type II Diabetes Mellitus Who Are Inadequately Controlled On Insulin Condition(s): Non-Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: This 24-week study will compare the effects of adding the drug rosiglitazone (2mg and 4mg) or placebo to insulin in patients with Type 2 diabetes mellitus (non-insulin-dependent) who have not achieved their blood glucose goal using insulin alone. Phase(s): Phase III

228 Insulin

Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00054782 •

Study of the Effects of Vitamin C on Patients with Type 2 Diabetes Condition(s): Diabetes Mellitus, Non-Insulin Dependent; Non-Insulin Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: Diabetes is a disease characterized by decreased sensitivity to the action on insulin to promote sugar (glucose) use and blood vessel relaxation (vasodilation) in muscle. Insulin's ability to cause blood vessel relaxation is controlled, in part, by nitric oxide (NO). Nitric oxide is a substance produced by the cells lining blood vessel walls (endothelium). Increased blood flow to the muscle accounts for increased sugar (glucose) to areas of the body. Therefore, if the cells of blood vessel walls (endothelium) are not functioning properly it may contribute to insulin resistance. Injections of Vitamin C directly into the arteries have been shown to improve blood vessel reaction to nitric oxide in diabetic patients. Researchers believe this may be due to Vitamin C's ability to increase the levels of nitric oxide in blood vessels. The goal of this study is to determine the effects of vitamin C on both insulin sensitivity and endothelium function of patients with type 2 diabetes. An additional goal of the study is to determine the effects of vitamin C on patients with vitamin C deficiency. Patients participating in this study will undergo a series of testes to determine insulin sensitivity and blood vessel reactivity. Patients will be divided into two groups. One group will receive doses of oral vitamin C. The other group will receive doses of a placebo (inactive pill not containing vitamin C). Patients will receive the medications for four weeks and then be tested again for insulin sensitivity and blood vessel reactivity. Researchers believe that doses of vitamin C in diabetics or patients with vitamin C deficiency will improve insulin sensitivity and function of endothelium. Results gathered form this study may provide information about vitamin C levels in diabetics and may lead to the development of new therapies to treat insulin resistance and endothelium dysfunction. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001870

•

The ORIGIN Trial (Outcome Reduction with Initial Glargine Intervention) Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): Aventis Pharmaceuticals Purpose - Excerpt: To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either IFG, IGT or early type 2 diabetes; To determine whether omega-3 fatty acids can reduce cardiovascular mortality in people with IFG, IGT or early type 2 diabetes. Phase(s): Phase III

Clinical Trials 229

Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069784 •

Insulin Action: Role of Skeletal Muscle and Insulin-Mediated Blood Flow Condition(s): Hypertension Study Status: This study is not yet open for patient recruitment. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: The overall objective of this proposal is to examine the contribution of changes in total body fat, enhancement in insulin-mediated vasodilatation and enhancement in endothelium-derived nitric oxide production to the improvements in metabolic insulin action. In addition, the study will track whether these improvements are related to changes in blood pressure. Phase(s): Phase I Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018304

•

Patterns and natural history of insulin secretion in islet cell transplant recipients and controls Condition(s): Diabetes Mellitus Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Center for Research Resources (NCRR); Juvenile Diabetes Research Foundation Purpose - Excerpt: This grant is to study patients that have received a kidney transplant AND an Islet Cell transplant and to discover how the transplant is functioning. We will seek to have several patients who have had a kidney transplant but do NOT have either type of diabetes. These patients will serve as the "control group" since they will also be on immunosuppressive medications but are not affected by abnormal blood sugars. This will allow investigators to develop an understanding of how these immunosuppressive medications affect glucose metabolism (blood sugar levels) and insulin utilization (how the body uses insulin). Phase(s): Phase I Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018122

•

Rosiglitazone and exercise training: effects on HIV-infected people with insulin resistance, hypertriglyceridemia, and adipose tissue maldistribution Condition(s): HIV Infections; Insulin Resistance Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Center for Research Resources (NCRR); The Campbell Foundation

230 Insulin

Purpose - Excerpt: Several complications have become prevalent in people living with HIV/AIDS, including increased blood sugar, increased blood fats and cholesterol, and fat tissue redistribution. The causes of these complications are not well understood and effective treatments have not been identified. We propose to test the efficacy and safety of 2 treatments for these complications in people living with HIV/AIDS: aerobic, weight lifting exercise training, and a new insulin-sensitizing agent called rosiglitazone (Avandia). Exercise and rosiglitazone have been effective and moderately safe when used in HIV-seronegative people with diabetes, but a specific trial is needed to test efficacy and safety in people living with HIV/AIDS. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00025753

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “insulin” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

•

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

•

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

•

For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

•

For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

•

For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

•

For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

•

For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

Clinical Trials 231

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

•

For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

•

For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

•

For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

•

For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

•

For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

•

For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

233

CHAPTER 6. PATENTS ON INSULIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “insulin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on insulin, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Insulin By performing a patent search focusing on insulin, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We

9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

234 Insulin

will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on insulin: •

3-aryl propionic acid derivatives and analogs Inventor(s): Alstermark; Eva-Lotte Lindstedt (Goteborg, SE), Andersson; Kjell (Fjar.ang.s, SE), Boije; Maria (Torslanda, SE), Gottfries; Johan (Goteborg, SE), Inghardt; Tord (Frilles.ang.s, SE), Li; Lanna (Goteborg, SE) Assignee(s): AstraZeneca AB (Sodertalje, SE) Patent Number: 6,630,600 Date filed: July 20, 1999 Abstract: Novel 3-aryl propionic acid derivatives and analogs, process and intermediate for their manufacture, pharmaceutical preparations containing them and the use of the compounds in clinical conditions associated with insulin resistance. Excerpt(s): The present invention relates to certain novel 3-aryl-2-hydroxypropionic acid derivatives and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them. Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver, prevails in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterized by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis. Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths. Web site: http://www.delphion.com/details?pn=US06630600__

•

Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders Inventor(s): Boueres; Julia K. (Piscataway, NJ), Desai; Ranjit C. (Kendall Park, NJ), Koyama; Hiroo (Hoboken, NJ), Miller; Daniel J. (Edison, NJ), Sahoo; Soumya P. (Old Bridge, NJ) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 6,645,997 Date filed: September 24, 2001 Abstract: A class of benzopyrancarboxylic acid derivatives comprises compounds that are potent agonists of PPAR alpha and/or gamma, and are therefore useful in the treatment, control or prevention of non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, obesity, vascular restenosis, inflammation, and other PPAR alpha and/or gamma mediated diseases, disorders and conditions.

Patents 235

Excerpt(s): The instant invention is concerned with benzopyrancarboxylic acids and related heterocyclic compounds and pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment and prevention of Type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes (NIDDM), of conditions that are often associated with this disease, and of lipid disorders. Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulinsensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance. Web site: http://www.delphion.com/details?pn=US06645997__ •

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and prostate cancer risk Inventor(s): Giovannucci; Edward (Wakefield, MA), Pollak; Michael N. (Montreal, CA), Stampfer; Meir J. (Brookline, MA) Assignee(s): Lady Davis Institute (Montreal, CA), The Brigham & Women's Hospital, Inc. (Boston, MA) Patent Number: 6,645,770 Date filed: March 14, 2001 Abstract: Methods of predicting a propensity to developing prostate cancer are presented. The method consists of measuring the IGF status of individual. Individuals with high IGF status, as compared with normal reference range values, are at increased risk for developing prostate cancer. More particularly, the IGF status may be determined by measuring IGF-I levels and/or IGFBP-3 levels. High IGF and low IGFBP levels are indicative of a high IGF status. A method of determining the prognosis of existing prostate cancers or of monitoring disease progression involves determining the IGF/PSA status of an individual. Individuals with a high IGF/PSA status (both high IGF status and high PSA levels) tend to develop severe prostate cancer and have a poorer overall prognosis. Excerpt(s): The present invention relates to a method for assessing the risk of developing prostate cancer in an individual. Increased risk for prostate cancer is correlated with high insulin-like growth factor status (IGF status). Specifically; the method involves

236 Insulin

measurement of IGF-I and/or insulin-like growth factor binding protein-3 (IGFBP-3) in a specimen. High levels of IGF and/or low levels of IGFBP correlate with increased risk of developing prostate cancer. In an alternative embodiment, the method involves determining the IGF/PSA status of an individual wherein the determination of IGF status is combined with a measurement of prostate specific antigen (PSA) levels. The IGF/PSA status provides an improved method of assessing the prognosis of existing prostate cancer. Furthermore, novel treatment modalities are suggested by the discovery of the link between IGF-axis component levels and prostate cancer that involve modulating IGF-axis component levels. Web site: http://www.delphion.com/details?pn=US06645770__ •

Combination therapeutic compositions and method of use Inventor(s): Chen; Jin-Long (Foster City, CA), Jaen; Juan C. (Burlingame, CA) Assignee(s): Tularik Inc. (South San Francisco, CA) Patent Number: 6,653,332 Date filed: May 2, 2001 Abstract: The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones,.alpha.-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I. Excerpt(s): In general, the present invention relates to pharmaceutical compositions, and more particularly, to pharmaceutical compositions for the treatment of diabetes mellitus using combination therapy. Diabetes mellitus is a term generally used to refer to various pathological states characterized by hyperglycemia and altered metabolism of lipids, carbohydrates and proteins. These conditions are also often associated with other comorbidities, such as obesity and an increased risk of cardiovascular disease. By some estimates, as many as 600,000 new individuals become clinically diabetic every year in the United States. Diabetic conditions are generally classified as either insulindependent diabetes mellitus (IDDM, Type I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM, Type II diabetes). There are also less common clinical pathologies that are associated with diabetic conditions, such as gestational maturity-onset diabetes of youth (MODY), tropical diabetes secondary to chronic pancreatis, diabetes secondary to pancreatic disease or surgery, and diabetes secondary to endocrinopathies. Web site: http://www.delphion.com/details?pn=US06653332__

Patents 237

•

Diagnostic screens for type 1 diabetes (IDDM) Inventor(s): Corkey; Barbara E. (Boston, MA), Husni; Nicholas R. (Boston, MA) Assignee(s): Boston Medical Center Corporation (Boston, MA) Patent Number: 6,620,583 Date filed: July 9, 2002 Abstract: The present invention features a method for identifying genes or proteins important in insulin-dependent diabetes mellitus (IDDM). The genes or proteins are useful in identifying IDDM-susceptible individuals, and in identifying and testing potential therapeutic agents for the treatment of IDDM. Excerpt(s): Approximately 16 million people (roughly 6% of the population) in the United States suffer from diabetes. Diabetes is the seventh leading cause of death (sixth leading cause of death by disease) in the United States claiming approximately 200,000 lives each year. Moreover, diabetes is one of the most costly health problems in America, running upwards of $92 billion in health care costs annually. Life-threatening complications associated with diabetes include cardiovascular disease and stroke, high blood pressure, blindness, kidney disease, nerve disease and amputation. Of the 16 million diabetics in the United States, approximately 5-10% suffer from IDDM (InsulinDependent Diabetes Mellitus) otherwise known as Type 1 diabetes. At least 30,000 new cases of IDDM are diagnosed each year. Persons with IDDM fail to produce insulin and, accordingly, are required to take daily insulin injections in order to stay alive. Many people are unaware that they have diabetes until they develop one or more of its lifethreatening complications. Accordingly, much biomedical research has focussed on the cause and development of diabetes with the hope that having a better understanding of the disease will ultimately aid in earlier detection and/or better therapeutic treatments. With regards to IDDM or Type 1 diabetes, three major theories have been advanced to account for the pathogenesis of the disease. The first is that IDDM is an inherited, or genetic disease. The second, that IDDM results from autoimmunity. The third theory states that IDDM is brought about by an environmental insult, presumably viral (Cotran (1989) Robbins Pathologic Basis of Disease 994-1005; Foster (1991) Harrison's Principles of Internal Medicine 1739-1759). Most agree however, that it is a combination of elements of all three theories that eventuates in IDDM, rather than each of the three acting independently in different individuals. There is much evidence to support the theory that IDDM is an inherited disease. IDDM tends to aggregate in families, meaning that if one individual in a given family has the disease, each other member of the family has a greater chance of developing it. Certain HLA types, notably those of the D region of chromosome 6, carry an increased risk of IDDM (Cox et al. (1994) Diabetologia 37:500503). Despite the presence of this genetic evidence, the facts remain that IDDM has a low prevalence of direct vertical transmission, and that the concordance rate of IDDM in monozygotic twins is only 20% (Cotran supra; Foster supra). This indicates that something more complex than simple Mendelian genetics is operating to cause the disease. Web site: http://www.delphion.com/details?pn=US06620583__

238 Insulin

•

Diphenylethylene compounds Inventor(s): Dey; Debendranath (Fremont, CA), Medicherla; Satyanarayana (Cupertino, CA), Nag; Bishwajit (Fremont, CA) Assignee(s): Calyx Therapeutics, Inc. (Hayward, CA) Patent Number: 6,624,197 Date filed: August 17, 2000 Abstract: Novel diphenylethylene and styrenes are provided which are administered orally to decrease blood glucose levels in rats. The glucose tolerance in insulin resistant rats is also shown, as well as lowering of triglyceride levels in serum insulin resistant, hyperinsulinemic and hypertriglycedemic rats. The compounds are orally effective antidiabetic agents that potentially may reduce abnormality of glucose and lipid metabolism in diabetes. Excerpt(s): The field of the invention is novel diphenylethylene compounds and their use for treatment of diabetes. Extracts of the leaves, flowers, and gum of the tree Pterocarpus marsupium Roxb. (Leguminosae), also known as the Indian Kino Tree, have been used traditionally for the treatment of diarrhea, toothaches, fever and urinary and skin infections. Extracts of the bark have been long regarded as useful for the therapy of diabetes. Hypoglycemic activity of a naturally occurring pterostilbene, trans1-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-ethylene, isolated from the heartwood of pterocarpus marsupium as been reported by Manickam et al., J. Nat. Prod., 1997, 60:609610. However, this pterostilbene is water insoluble and has not been shown to be efficacious in the treatment of diabetes, particularly in instances where insulin is present but inactive. The cause of diabetes is yet unknown, although both genetics and environment appear to be factors. Insulin dependent (Type I) and non-insulin dependent (Type II) are the types of diabetes. Type I is an autonomic immune disease in which the responsible autoantigen is still unknown. Patients of Type I need to take insulin intravenously to survive. However, Type II diabetes, the more common form of the disease, is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced within the body. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown. Web site: http://www.delphion.com/details?pn=US06624197__

•

Dispenser for patient infusion device Inventor(s): Flaherty; J. Christopher (Topsfield, MA), Garibotto; John T. (Charlestown, MA), Gregory; Christopher Carter (Newtown, PA), Mahoney; Derek Dwayne (Manalapan, NJ), Margicin; John Michael (Langhorne, PA), O'Mara; Kerry Dennis (Lambertville, NJ) Assignee(s): Insulet Corporation (Beverly, MA) Patent Number: 6,656,158 Date filed: April 23, 2002 Abstract: A device for delivering fluid, such as insulin for example, to a patient. The device includes an exit port assembly, a syringe-like reservoir including a side wall extending towards an outlet connected to the exit port assembly. A threaded lead screw is received in the reservoir and a plunger has an outer periphery linearly slideable along

Patents 239

the side wall of the reservoir and an inner periphery threadedly received on the lead screw. The plunger is non-rotatable with respect to the side wall such that rotating the lead screw causes the plunger to advance within the reservoir and force fluid through the outlet. The device also includes a dispenser having a return element for causes rotation of the lead screw, and a shape memory element. A changeable length of the shape memory element decreasing from an uncharged length to a charged length resets the return element. Excerpt(s): The present invention relates generally to medical devices, systems and methods, and more particularly to small, low cost, portable infusion devices and methods that are useable to achieve precise, sophisticated, and programmable flow patterns for the delivery of therapeutic liquids such as insulin to a mammalian patient. Even more particularly, the present invention is directed to a dispenser for a fluid delivery device that utilizes a shape memory element. Today, there are numerous diseases and other physical ailments that are treated by various medicines including pharmaceuticals, nutritional formulas, biologically derived or active agents, hormonal and gene based material and other substances in both solid or liquid form. In the delivery of these medicines, it is often desirable to bypass the digestive system of a mammalian patient to avoid degradation of the active ingredients caused by the catalytic enzymes in the digestive tract and liver. Delivery of a medicine other than by way of the intestines is known as parenteral delivery. Parenteral delivery of various drugs in liquid form is often desired to enhance the effect of the substance being delivered, insuring that the unaltered medicine reaches its intended site at a significant concentration. Also, undesired side effects associated with other routes of delivery, such as systemic toxicity, can potentially be avoided. Often, a medicine may only be available in a liquid form, or the liquid version may have desirable characteristics that cannot be achieved with solid or pill form. Delivery of liquid medicines may best be accomplished by infusing directly into the cardiovascular system via veins or arteries, into the subcutaneous tissue or directly into organs, tumors, cavities, bones or other site specific locations within the body. Web site: http://www.delphion.com/details?pn=US06656158__ •

Human glucose-6-phosphatase molecules and uses thereof Inventor(s): Chen; Hong (Newton, MA) Assignee(s): Millennium Pharmaceuticals, Inc. (Cambridge, MA) Patent Number: 6,623,947 Date filed: June 4, 2001 Abstract: The invention provides isolated nucleic acids encoding human pancreatic isletspecific glucose-6-phosphatase proteins and nucleic acids having diagnostic, preventive, therapeutic, and other uses. These nucleic acids and proteins are useful for diagnosis, prevention, and therapy of a number of human and other animal disorders. The invention also provides antisense nucleic acid molecules, expression vectors containing the nucleic acid molecules of the invention, host cells into which the expression vectors have been introduced, and non-human transgenic animals in which a nucleic acid molecule of the invention has been introduced or disrupted. The invention still further provides isolated polypeptides, fusion polypeptides, antigenic peptides, and antibodies. Diagnostic, screening, and therapeutic methods utilizing compositions of the invention are also provided. The nucleic acids and polypeptides of the present invention are useful as modulating agents in regulating a variety of cellular processes, including those

240 Insulin

which are aberrant in diabetes and other disorders associated with pancreatic dysfunction. The invention includes methods of modulating secretion of pancreatic hormones such as insulin and glucagon, and these methods can be used to alleviate disorders (e.g., diabetes and hyperinsulinemia) associated with aberrant secretion of these hormones. Excerpt(s): Glucose-6-phosphatase (G6Pase; EC 3.1.3.9) catalyzes hydrolysis of glucose6-phosphate (G6P), yielding glucose. This reaction is the terminal step in the gluconeogenic and glycogenolytic pathways. Most cells of the body are able to convert glucose absorbed from the blood stream to G6P, thereby preventing facilitated diffusion of the glucose moiety out of the cell. Some cells, such as liver cells, possess G6Pase activity, whereby G6P can be converted to glucose and released to the bloodstream or used by the cell for metabolism. For example, formation of glucose in the liver from hepatically-stored glycogen (i.e., involving intermediate hydrolysis of G6P by G6Pase) is an important mechanism by which blood glucose is maintained at a normal level between meals. Maintenance of normal blood glucose levels is important for nutrition of certain tissues (e.g., brain and other nervous system tissues and gonadal germinal epithelium) which are substantially incapable of metabolizing other energy sources such as fatty acids or amino acids. Lipid and protein metabolism can be undesirable, in that such metabolism depletes bodily stores of lipids and proteins, and in that the byproducts of such metabolism (e.g., certain lipoprotein-containing particles) can cause or contribute to pathological conditions (e.g., deposition of lipoprotein plaque in arteries). Thus, in addition to providing nutrition to tissues which metabolize glucose almost exclusively, maintenance of normal blood glucose levels prevents physiologically inappropriate reliance of the body on non-carbohydrate catabolic routes. Web site: http://www.delphion.com/details?pn=US06623947__ •

Human glucose-dependent insulin-secreting cell line Inventor(s): Perfetti; Riccardo (Los Angeles, CA) Assignee(s): Cedars-Sinai Medical Center (Los Angeles, CA) Patent Number: 6,642,003 Date filed: August 2, 2001 Abstract: Disclosed herein is a novel cell line of human pancreatic cells that secrete insulin in a glucose-dependent manner. The cell line comprises pancreatic cells, such as PANC-1 cells, which are transfected so as to express IDX-1 and cultured in GLP-1. The cell line may be used to investigate the function and development of pancreatic cells, as well as to test the efficacy of drugs that stimulate insulin secretion. Excerpt(s): Embodiments of the present invention are directed to a human pancreatic cell line transfected so as to express.beta.-cell differentiation factor IDX-1. Cells so transfected respond to glucagon-like peptide-1 by differentiating into insulinsecreting.beta. cells. Embodiments of the present invention are directed to a human pancreatic cell line transfected so as to express.beta.-cell differentiation factor IDX-1. Cells so transfected respond to glucogon-like/peptide-1 by differentiating into insulinsecreting.beta.cells. Insulin is essential for proper metabolism in humans: in addition to its familiar role as the chief regulator of blood sugar levels in humans, it is essential for carbohydrate, lipid, and protein metabolism, as well. Pancreatic beta (.beta.) cells of the islets of Langerhans, epithelial cells dispersed throughout the pancreas, secrete insulin.

Patents 241

When.beta. cells are destroyed or their function impaired, insulin production declines, and diabetes results. Web site: http://www.delphion.com/details?pn=US06642003__ •

Hypoglycemic sulfonyl pyrazolones and pyrazolines Inventor(s): Dominianni; Samuel James (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 6,617,342 Date filed: April 16, 2002 Abstract: This invention provides compounds and their pharmaceutically acceptable salts, pharmaceutical formulation of said compounds and methods for treating hyperglycemia associated with non-insulin dependant diabetes and for treating hyperlipidemia. Excerpt(s): This invention relates to the treatment and control of hyperglycemia, such as occurs in non-insulin-dependent diabetes mellitus (NIDDM). This invention also relates to treatment and control of hyperlipidemia. The disease, diabetes mellitus, is recognized in two forms. Type I diabetes requires exogenous insulin for control of the disease because it appears that endogenous production of insulin by the Isles of Langerhans in the pancreas is extremely poor or non-existent. Type I diabetes is often referred to as insulin-dependent diabetes mellitus (IDDM). Type II, non-insulin-dependent diabetes mellitus (NIDDM), is characterized by defects of insulin sensitivity in peripheral tissues such as adipose tissue and muscle, as described by J. E. Gerich in New Engl. J. Med., 321, 1231-1245 (1989). Hyperlipidemia is often observed in diabetics (Diabetes Care, 18, Supplement 1, 86-93, 1995). The combination of hyperlipidemia and hyperglycemia greatly increases the risk of cardiovascular diseases in diabetics. Successful treatment of hyperlipidemia and hyperglycemia in diabetics is needed urgently. Web site: http://www.delphion.com/details?pn=US06617342__

•

Insulin delivery enhanced by coached breathing Inventor(s): Gonda; Igor (South Yarra, AU), Rubsamen; Reid M. (Alamo, CA) Assignee(s): Aradigm Corporation (Hayward, CA) Patent Number: 6,647,987 Date filed: June 18, 2002 Abstract: The need for the delivery of insulin by injection can be reduced or eliminated by a method whereby an aerosolized insulin formulation is delivered to a patient's lungs and the rate at which the insulin is absorbed into the blood is increased by the use of an inhale-exhale breathing maneuver. Particles of insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. The rate of absorption is enhanced by instructing the patient to inhale maximally and thereafter exhale maximally. The insulin is delivered to the patient from a hand-held, self-contained device which automatically releases an aerosolized burst of formulation. The device includes a sensor which is preferably electronic which measures inspiratory flow and volume which measurement can be used to control the point of drug release. The sensor can also assist the patient in the inhale-exhale maneuver.

242 Insulin

Excerpt(s): This invention relates generally to a method of, aerosolized drug delivery. More specifically, this invention relates to coached breathing methodology useful in the controlled intrapulmonary delivery of insulin alone or in combination with other treatment methodologies which are combined to significantly reduce or eliminate the need for administering insulin by injection. Diabetes Mellitus is a disease affecting approximately 7.5 million people in the United States. The underlying cause of this disease is diminished or absent insulin production by the Islets of Langerhans in the pancreas. Of the 7.5 million diagnosed diabetics in the United States, approximately one-third are treated using insulin replacement therapy. Those patients receiving insulin typically self-administer one or more doses of the drug per day by subcutaneous injection. Insulin is a polypeptide with a nominal molecular weight of 6,000 Daltons. Insulin has traditionally been produced by processing pig and cow pancreas to allow isolation of the natural product. More recently, recombinant technology has made it possible to produce human insulin in vitro. It is the currently common practice in the United States to institute the use of recombinant human insulin in all of those-patients beginning insulin therapy. It is known that most proteins are rapidly degraded in the acidic environment of the GI tract. Since insulin is a protein which is readily degraded in the GI tract, those in need of the administration of insulin administer the drug by subcutaneous injection (SC). No satisfactory method of orally administering insulin has been developed. The lack of such an oral delivery formulation for insulin creates a problem in that the administration of drugs by injection can be both psychologically and physically painful. Web site: http://www.delphion.com/details?pn=US06647987__ •

Insulin derivatives Inventor(s): Brandt; Jakob (Bronshoj, DK), Hansen; Per Hertz (Lyngby, DK), Havelund; Svend (Bagsvaerd, DK), Jonassen; Ib (Valby, DK), Kaarsholm; Niels Christian (Vanlose, DK), Kurtzhals; Peter (Brookline, MA), Markussen; Jan (Herlev, DK) Assignee(s): Novo Nordisk A/S (Bagsvaerd, DK) Patent Number: 6,620,780 Date filed: May 21, 2001 Abstract: The present invention relates to insulin derivatives in which a lipophilic group having from 12 to 40 carbon atoms is attached to the.alpha.-amino group of the N-terminal amino acid in the B-chain or to the carboxy group of the C-terminal amino acid in the B-chain have a protracted profile of action. Excerpt(s): The present invention relates to novel human insulin derivatives which are soluble and have a protracted profile of action, to a method of providing such derivatives, to pharmaceutical compositions containing them, and to the use of such insulin derivatives in the treatment of diabetes. Many diabetic patients are treated with multiple daily insulin injections in a regimen comprising one or two daily injections of a protracted insulin to cover the basal requirement supplemented by bolus injections of a rapid acting insulin to cover the meal-related requirements. Protracted insulin compositions are well known in the art. Thus, one main type of protracted insulin compositions comprises injectable aqueous suspensions of insulin crystals or amorphous insulin. In these compositions, the insulin compounds utilized typically are protamine insulin, zinc insulin or protamine zinc insulin. Web site: http://www.delphion.com/details?pn=US06620780__

Patents 243

•

Insulin preparations for pulmonary delivery containing menthol Inventor(s): Havelund; Svend (Bagsv.ae butted.rd, DK) Assignee(s): Novo Nordisk A/S (Bagsvaerd, DK) Patent Number: 6,635,617 Date filed: October 15, 1999 Abstract: A stable, aqueous insulin formulation suitable for pulmonary delivery is disclosed. The formulation has increased convenience for the patient and improved bioavailability of insulin. Excerpt(s): The present invention relates to stable, aqueous insulin formulations suitable for pulmonary delivery with increased convenience for the patient and improved bioavailability of insulin. Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes. Since the introduction of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycaemia levels, diabetic patients often practice multiple injection therapy, whereby insulin is administered with each meal. Web site: http://www.delphion.com/details?pn=US06635617__

•

Insulin-like growth factor agonist molecules Inventor(s): Clark; Ross G. (Auckland, NZ), Lowman; Henry B. (El Granada, CA), Robinson; Iain C.A.F. (St. Albans, GB) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 6,620,789 Date filed: November 28, 2000 Abstract: Compounds are provided that inhibit the interaction of an IGF with any one of its binding proteins and not to a human IGF receptor. These IGF agonist compounds, which include peptides, are useful to increase serum and tissue levels of active IGFs in a mammal. Excerpt(s): This invention relates to molecules useful as agonists of the insulin-like growth factors (IGFs). More particularly, these molecules inhibit the interaction of an IGF with one or more of its IGF binding proteins. Such molecules can be used, for example, in any methods where the IGFs are used, for example, in treating hyperglycemic, obesity-related, neurological, cardiac, renal, immunologic, and anabolic disorders. There is a large body of literature on the actions and activities of IGFs (IGF-I, IGF-II, and IGF variants). Human IGF-I is a 7649-dalton polypeptide with a pI of 8.4 (Rinderknecht and Humbel, Proc. Natl. Acad. Sci. USA, 73: 2365 (1976); Rinderknecht and Humbel, J. Biol. Chem., 253: 2769 (1978)) belonging to a family of somatomedins with insulin-like and mitogenic biological activities that modulate the action of growth hormone (GH). Van Wyk et al., Recent Prog. Horm. Res., 30: 259 (1974); Binoux, Ann. Endocrinol., 41: 157 (1980); Clemmons and Van Wyk, Handbook Exp. Pharmacol., 57: 161 (1981); Baxter, Adv. Clin. Chem., 25: 49 (1986); U.S. Pat. No. 4,988,675; WO 91/03253; WO 93/23071. Like GH, IGF-I is a potent anabolic protein. See Tanner et al., Acta

244 Insulin

Endocrinol., 84: 681-696 (1977); Uthne et al., J. Clin. Endocrinol. Metab., 39: 548-554 (1974). See also Ross et al., Intensive Care Med., 19 Suppl. 2: S54-57 (1993), which is a review of the role of insulin, GH, and IGF-I as anabolic agents in the critically ill. IGF-I has hypoglycemic effects similar to those of insulin, but also promotes positive nitrogen balance. Underwood et al., Hormone Res., 24: 166 (1986); Guler et al., N. Engl. J. Med., 317: 137 (1987). Due to this range of activities, IGF-I is being tested in humans for such widely disparate uses as wound healing, treatment of diabetes, reversal of whole body catabolic states, treatment of heart conditions such as congestive heart failure, and treatment of neurological disorders. Guler et al., Proc. Natl. Acad. Sci. USA, 85: 48894893 (1988); Duerr et al., J. Clin. Invest., 95: 619-627 (1995); and Science, 264: 772-774 (1994). Web site: http://www.delphion.com/details?pn=US06620789__ •

Islet cell antigen 1851 Inventor(s): Hagopian; William A. (Seattle, WA), Jelinek; Laura J. (Seattle, WA), Kindsvogel; Wayne (Seattle, WA), LaGasse; James M. (Seattle, WA), Sheppard; Paul O. (Redmond, WA) Assignee(s): ZymoGenetics, Inc. (Seattle, WA) Patent Number: 6,627,735 Date filed: June 7, 2001 Abstract: A mammalian islet cell antigen polypeptide involved in the development of insulin-dependent diabetes mellitus (IDDM) is disclosed. This islet cell antigen polypeptide, 1851, was found to contain regions of homology to the protein tyrosine phosphatase family. Methods for diagnosis and treatment, including use in immunoprecipitation assays and the induction of immune tolerance using the recombinant mammalian polypeptides and antibodies specific to mammalian islet cell antigen 1851 polypeptides are presented. Excerpt(s): Detection of specific autoantigens in prediabetic individuals has been used as a predictive marker to identify, before clinical onset and significant.beta.-cell loss has occurred, those at greater risk of developing IDDM (Gorsuch et al., Lancet 2: 1363-65, 1981; Baekkeskov et al., J. Clin. Invest. 79: 926-34, 1987; Johnstone et al., Diabetologia 32: 382-86, 1989; Ziegler et al., Diabetes 38: 1320-25, 1989; Baekkeskov et al., Nature (Lond) 347: 151-56, 1990; Bonifacio et al., Lancet 335: 147-49, 1990; and Bingley et al. Diabetes 43: 1304-10, 1994). Antibodies to the 40 kD, and more particularly the 37 kD, ICA fragments are detected when clinical onset of IDDM is imminent and are found to be closely associated with IDDM development (Christie et al., Diabetes 41: 782-87, 1992). Diabetic sera containing antibodies specific to the 40 kD fragment were recently found to bind to the intracellular domain of the protein tyrosine phosphatase, IA-2/ICA512 (Lu et al., Biochem. Biophys. Res. Comm. 204: 930-36, 1994; Lan et al., DNA Cell Biol. 13: 505-14, 1994; Rabin et al., J. Immunol. 152: 3183-88, 1994; Payton et al., J. Clinc. Invest. 96: 150611, 1995; and Passini et al., Proc. Natl. Acad. Sci. USA 92: 9412-16, 1995). Antibodies specific to the 37 kD fragment are thought to bind either to a posttranslational in vivo modification of IA-2/ICA512 or a different, but probably related, protein precursor (Passini et al., ibid.). Detection of diabetes-associated autoantigens, especially combinations of autoantigens, genotypes, such as HLA DR and HLA DQ, and loci, such as the polymorphic region in the 5' flanking region of the insulin gene; in prediabetic individuals have been shown to be useful predictive markers of IDDM, see for example, Bell et al., (Diabetes 33:176-83, 1984); Sheehy et al., (J. Clin. Invest. 83:830-35, 1989); and

Patents 245

Bingley et al., (Diabetes 43: 1304-10, 1994). There is therefore a need in the art for autoantigens that would serve to improve detection and diagnosis of IDDM. The present invention fulfills this need by providing novel autoantigens as well as related compositions and methods. The autoantigens of the present invention represent a new.beta.-cell antigen. The present invention also provides other, related advantages. Web site: http://www.delphion.com/details?pn=US06627735__ •

Limiting weight gain of cats by feeding carbohydrate source that excludes rice Inventor(s): Sunvold; Gregory D. (Eaton, OH) Assignee(s): The Procter & Gamble Company (Cincinnati, OH) Patent Number: 6,630,159 Date filed: March 27, 2001 Abstract: A process is provided for limiting weight gain in cats. The process includes feeding the cat a pet food composition that includes a source of protein, a source of fat, and a source of carbohydrates from a grain source that excludes rice. Use of preferred low glycemic index grain sources that comprise a blend of corn and sorghum; a blend of corn, sorghum, and barley; or a blend of corn, sorghum, and oats, has the effect of decreasing the postprandial blood glucose and insulin response of the cat as compared to when feeding a rice-based diet. The result is that the animal becomes satiated and voluntarily decreases its intake of food, causing less weight gain. This effect is even more marked when the composition is fed to male cats. Excerpt(s): This invention relates to a process of administering a pet food composition to prevent obesity in companion animals, such as cats and dogs. More particularly, the invention relates to a process for limiting weight gain in cats. The invention is further directed to a process for decreasing the postprandial blood glucose and insulin response in cats to promote satiety and a voluntary decrease in food intake. Obesity is a significant health concern in companion animals. Veterinary care professionals have reported that approximately 20-40% of the pets in their care are overweight. These animals bear a greater risk for health problems associated with the respiratory, cardiovascular, and skeletal systems. More particularly, obese feline patients have demonstrated greater susceptibility to diseases such as diabetes mellitus, osteoarthritis, ligament injuries, perineal dermatitis, cardiomyopathy, and hepatic lipidosis. Accordingly, new technologies meeting the health needs of obese feline patients are in high demand by pet owners and veterinarians alike. The causes of feline obesity include sedentary lifestyle and confinement indoors, as well as improper nutrition, genetic predisposition, and hormonal disorders such as thyroid and pituitary gland dysfunction. Moreover, spayed and neutered cats often exhibit a decrease in their physical activity and metabolism and therefore, have a greater tendency to gain weight. Web site: http://www.delphion.com/details?pn=US06630159__

246 Insulin

•

Method and insulin pump for providing a forgotten bolus warning Inventor(s): Jones; Steven Paul (Rochester, MN), Williams; Robert Russell (Rochester, MN) Assignee(s): International Business Machines Corporation (Armonk, NY) Patent Number: 6,650,951 Date filed: June 19, 2000 Abstract: A method and apparatus are provided for providing a forgotten bolus warning for an insulin pump user. User selections for mealtimes are received and stored. A user selection for a warning wait period is received and stored. When a time past a mealtime plus the user selection for the warning wait period is identified, checking for a bolus having been taken is performed. Responsive to no bolus having been taken, the user is alerted with the forgotten bolus warning. The user is alerted with the forgotten bolus warning by an audible, visual, or tactile warning for a programmable period of time. The user selections for mealtimes are received and stored on a daily basis for each day of the week. The user selection for a warning wait period can be received and stored independently for each meal. Excerpt(s): The present invention relates generally to insulin pumps, and more particularly, relates to a method and apparatus for providing a forgotten bolus warning for an insulin pump user. Various insulin pumps are commercially available. To achieve the best control of diabetes, many diabetics are turning to use of insulin pumps. An insulin pump is a device that periodically dispenses very small amounts of insulin according to a preprogrammed profile set by the user to cover basal insulin needs. Basal insulin takes care of or covers glucose produced by the body (liver) on a continuous basis. When a diabetic person consumes food, the diabetic person needs to estimate the amount of carbohydrate content in the food and program the pump to administer a bolus amount of insulin to cover the carbohydrates in the meal. For example, if known for a particular individual that one unit of insulin covers 10 grams of carbohydrates, and the meal has 100 grams of carbohydrates, at mealtime the individual would program the pump to administer a bolus amount of 10 units of insulin. Because the bolus amount varies per meal and the diabetic person may skip a meal, an insulin pump is not preprogrammed to administer a bolus amount of insulin. It is quite easy for a diabetic person to fail to program a bolus at mealtime. The failure to program the bolus can be either a lapse of memory or an error, such as not pushing the pump's button hard enough. If the bolus is not administered, blood sugar levels typically will rise to unhealthy and perhaps dangerous levels. Even if the person feels the high blood sugar effects, by then some harm or risk for diabetic complications have occurred. Usually a diabetic does not sense high blood glucose until it is above 400 mg/dl, whereas the usual target range is 70 mg/dl to 120 mg/dl. While one could take more frequent blood sugar readings with available blood testing equipment, such testing is expensive and painful. Web site: http://www.delphion.com/details?pn=US06650951__

Patents 247

•

Method for identifying compounds for treatment of insulin resistance Inventor(s): Shoelson; Steven (Natick, MA) Assignee(s): Joslin Diabetes Center, Inc. (Boston, MA) Patent Number: 6,630,312 Date filed: February 2, 2001 Abstract: The invention features a method of identifying, evaluating or making a compound or agent, e.g., a candidate compound or agent, for treatment of a disorder characterized by insulin resistance. The method includes evaluating the ability of a compound or agent to bind IKK-.beta. or modulate IKK-.beta. activity, to thereby identify a compound or agent for the treatment of a disorder characterized by insulin resistance. The invention also features compounds for treating insulin resistance identified by such methods, and methods of treating a subject having a disorder characterized by insulin resistance by administering such agents. Excerpt(s): Insulin resistance refers to a decreased capacity of circulating insulin to regulate nutrient metabolism. Individuals with insulin resistance are predisposed to developing Type 2 diabetes, and insulin resistance is an integral feature of its pathophysiology. Greater than normal levels of insulin are secreted to overcome target tissue resistance, which leads to the eventual failure of pancreatic.beta. cells in predisposed individuals. Insulin resistance also occurs in hypertension, cardiovascular disease and dyslipidemia, suggesting an etiologic relationship that is referred to as the metabolic syndrome or syndrome X. The prevalence of insulin resistance is remarkably high, particularly in ageing adult populations (National Diabetes Data Group, Diabetes in America (National Institutes of Diabetes and Digestive Diseases, National Institutes of Health, USA, 1994), and rising--most rapidly in the young (Mokdad et al. (2000) Diabetes Care 23:1278-1283). Nevertheless, only rare genetic causes have been identified. Environmental factors, including sedentary lifestyle, obesity, and increased age induce insulin resistance, whereas exercise and weight loss reverse it. The present invention is based, in part, on the discovery that aspirin reverses insulin resistance in liver and fat cells, e.g., by targeting IKK-.beta. It has been discovered that insulin sensitivity is improved in vivo by modulating, e.g., reducing, IKK.beta. activity, e.g., by decreased protein expression. Thus, IKK-.beta. is a target for identifying compounds for the treatment of disorders associated with insulin resistance. Web site: http://www.delphion.com/details?pn=US06630312__

•

Method for reducing blood insulin levels by reducing in vivo cathepsin L activity Inventor(s): Chen; Jingming (Fremont, CA), Shi; Guo-ping (Palo Alto, CA), Yong; Hamilton H. (Castro Valley, CA) Assignee(s): NewMillennium Pharmaceutical, Inc. (Foster City, CA) Patent Number: 6,620,844 Date filed: February 14, 2001 Abstract: Methods and compositions are provided for modulating blood insulin levels of animals by targeting the gene and gene products of cathepsins, particularly cathepsins L, K, and S, and especially cathepsin L. The method comprises: administering to the animal an agent that reduces an in vivo level of cathepsin L activity such that the blood insulin level of the animal is reduced. The method can be used to treat

248 Insulin

hyperinsulinmia and related diseases such as insulin resistance, type II diabetes, and hyperglycermia. Excerpt(s): This invention relates to treatment of obesity and related diseases, such as hyperinsulinmia, hyperglycermia, hypertension, cardiovascular diseases, muscular dystrophy and infertility. More particularly, the invention relates to methods of treating obesity and non-insulin-dependent (type II) diabetes mellitus (NIDDM) by specifically targeting the genes and gene products of cathepsins. Obesity is the most important nutritional disorder in the western world, with the estimates of its prevalence ranging from 30% to 50% within the middle-aged population. Obesity is usually defined as a body weight more than 20% in excess of the ideal body weight. Severe obesity can be a chronic disease that affects an increasingly large number of people and requires longterm treatment to promote and sustain weight loss. Obesity is caused by accumulation of excess adipose tissue containing fat cells, or adipocytes, most predominately under the skin, in the abdominal cavity, in skeletal muscle, round the blood vessels, and in mammary gland. The adipose tissue of a normal 70-kg man contains about 15 kg of fat. Web site: http://www.delphion.com/details?pn=US06620844__ •

Method for searching physiologically active substances, process for producing these substances and drugs found by the searching method Inventor(s): Sakamoto; Kenji (25, Aza Kourokuzawa, Memeki, Yuuwa-machi, Kawabegun, Akita 010-1233, JP) Assignee(s): Nakoshi; Hideo (Tokyo, JP), Sakamoto; Kenji (Akita, JP) Patent Number: 6,624,287 Date filed: August 8, 2001 Abstract: A method for efficiently searching novel physiologically active substances under a certain predictability. This searching method comprises, among receptors of cells producing an antagonist to a substance in vivo or receptors of cells producing an antagonist to the cells per se, finding a receptor having amino acid sequences of two or more sizes by comparing the cDNA sequences of the receptor, and then examining which region in the longer receptor is missed in the shorter receptor by comparing the above cDNA sequences. By using this method, remedies for diabetes comprising a peptide having the amino acid sequence represented by SEQ ID NO:1 or 5, insulin production regulators comprising a peptide having the amino acid sequence represented by SEQ ID NO:2, and gastric secretion inhibitors comprising a peptide having the amino acid sequence represented by SEQ ID NO:3 or 4 are provided. Excerpt(s): The invention relates to a method for searching various types of novel physiologically active substances and a process for producing same, and drugs found by the searching method. In the prior art, the searching for unknown physiologically active substances involved analyzing constituents present in body fluids or tissues, identifying and isolating novel substances and investigating the physiological activity of the discovered novel substances. The method of the prior art described above consists of analyzing constituents present in the body, finding novel substances and investigating their physiological activities. However, the number of constituents present in the body is extremely high, and physiologically active substances are often present only in low concentrations, thereby making finding novel substances a difficult task. Further, because an overwhelming number of physiological reactions take place in the body, and thus, finding the nature of physiological activities the newly found substances have is

Patents 249

also difficult. Therefore, finding novel physiologically active substances with the method of the prior art is a difficult task. Web site: http://www.delphion.com/details?pn=US06624287__ •

Method for treating diabetes mellitus Inventor(s): Weinstein; Allan M. (9205 Pegasus Ct., Potomac, MD 20854), Weinstein; Robert E. (177 Commonwealth Ave., Boston, MA 02116) Assignee(s): none reported Patent Number: 6,652,838 Date filed: April 4, 2002 Abstract: A method for treating postprandial hyperglycemia in diabetes mellitus in a human which employs a combination of an aerosolizable topical insulin and a shortacting oral hypoglycemic agent as a regimen taken adjacent to mealtime. Excerpt(s): The present invention relates generally to the treatment of diabetes. Particularly, the present invention relates to the treatment of diabetes without the use of insulin injections. Diabetes mellitus is a chronic illness caused by a lack of an effective amount of insulin. It is manifested by the elevation of blood sugar. Diabetes mellitus is the fourth leading cause of death by disease in the United States and the leading cause of irreversible blindness and chronic renal failure. Treatment for diabetes is directed to lowering blood sugar, particularly after meals, and to preventing long term complications that include neuropathy, accelerated atherosclerosis, myocardial infarction, gangrene of the lower extremities, retinopathy and nephropathy. Diabetic individuals are typically required to comply with treatments over very long periods of time to avoid these complications. The two pharmacological modalities presently used to lower blood sugar are oral hypoglycemic (anti-diabetic) agents and insulin. Insulin replacement is presently accomplished by injection and is based upon the lack of insulin or limitation of its action in diabetes mellitus. Oral anti-diabetic agents are not chemically akin to insulin and their sugar-lowering mechanism differs from the action of direct insulin replacement. Oral hypoglycemic agents and insulin are, at present, therapeutically utilized alone or in concert with each other, according to the needs of the diabetic individual. Some individuals are best treated with more than one oral agent, with, or without insulin. Web site: http://www.delphion.com/details?pn=US06652838__

250 Insulin

•

N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboximidoyl and its use in the treatment of insulin resistance

chloride

Inventor(s): Barabas; Mihaly (Budapest, HU), Biro; Katalin (Budapest, HU), Csakai; Zita (Kunszentmiklos, HU), Kardos; Mihalyne (Veszprem, HU), Komaromi; Andras (Veszprem, HU), Koranyi; Laszlo (Budapest, HU), Kurthy; Maria (Balatonfured, HU), Marvanyos; Ede (Budapest, HU), Mogyorosi; Tamas (Kazincbarcika, HU), Nagy; Karoly (Budapest, HU), Nagy; Melinda (Veszprem, HU), Nagy; Zoltan (Budapest, HU), Szilbereky; Jeno (Budapest, HU), Torok; Magdolna (Mateszalka, HU), Urogdi; Laszlo (Budapest, HU) Assignee(s): Biorex Kutato es Fejleszto RT (Veszprem-Szabadsagpuszta, HU) Patent Number: 6,649,628 Date filed: December 18, 2001 Abstract: N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and the addition salts thereof, pharmaceutical compositions containing the same, methods of treating pathological insulin resistance, methods of treating pathological insulin resistance and pathological conditions associated therewith, and methods of treating pathological insulin resistance by simultaneously treating diabetes-induced chronic complications, especially retinopathy, neuropathy and nephropathy, and/or by simultaneously increasing pathologically decreased peripheral neuroregeneration caused by diabetes. Excerpt(s): An O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, its application in the treatment of insulin resistance, and the pharmaceutical preparation containing this derivative as effective agent. The invention relates to an O(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, the pharmaceutical use thereof and the pharmaceutical products containing this derivative as active ingredient. Namely, the invention relates to N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, as well as their acid addition salts. Furthermore, the invention also relates to the use of these compounds in the treatment of insulin resistance and the pharmaceutical products containing these derivatives as active ingredient. O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivatives are already known from European Patent Specification No. 0 417 210 B1. According to this patent specification, these compounds exhibit a selective beta blocking effect and are thus suitable for the treatment of diabetic angiopathy, more specifically, of diabetic retinopathy and nephropathy. Web site: http://www.delphion.com/details?pn=US06649628__ •

Naphthylsulfonic acids and related compounds as glucose uptake agonists Inventor(s): Kozlowski; Michael R. (Palo Alto, CA), Lum; Robert T. (Palo Alto, CA), Manchem; Prasad V. V. S. V. (South San Francisco, CA), Park; Jeong Weon (Emeryville, CA), Robinson; Louise (San Carlos, CA), Schow; Steven R. (Redwood Shores, CA), Shi; Songyuan (Fremont, CA), Spevak; Wayne R. (Albany, CA) Assignee(s): Telik, Inc. (Palo Alto, CA) Patent Number: 6,653,321 Date filed: July 28, 2000

Patents 251

Abstract: Methods for treating conditions associated with hyperglycemia, especially Type II diabetes, with novel naphthylsulfonic acids and related compounds. These compounds, as single stereoisomers or mixtures of stereoisomers, or their pharmaceutically acceptable salts, are useful in methods of stimulating the kinase activity of the insulin receptor, enhancing the activation of the insulin receptor by insulin, and stimulating the uptake of glucose into cells. A variety of antidiabetic compounds and pharmaceutical compositions comprising the antidiabetic compounds are also disclosed. Excerpt(s): The present invention relates to methods, pharmaceutical compositions, and compounds for enhancing insulin-dependent glucose uptake. The compounds of the invention activate the insulin receptor kinase, leading to an increased sensitivity to insulin and an increase in glucose uptake. The invention relates in particular to the use of the compounds in methods for the treatment of humans with hyperglycemia, and especially for the treatment of Type II diabetes. Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage. Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle and fat exhibit the insulin resistance (Haring and Mehnert, Diabetologia 36:176-182 (1993); Haring et al., Diabetologia, 37 Suppl 2:S149-54 (1994)). The resistance to insulin in Type II diabetes is complex and likely multifactorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals, and may be an underlying etiologic factor in the development of the disease (Reaven, Diabetes, 37:1595-1607 (1988)). Web site: http://www.delphion.com/details?pn=US06653321__ •

Nucleic acids and proteins of C. elegans insulin-like genes and uses thereof Inventor(s): Buchman; Andrew Roy (Berkeley, CA), Doberstein; Stephen Kohl (San Francisco, CA), Ferguson; Kimberly Carr (Pacifica, CA), Homburger; Sheila Akiko (Oakland, CA), Platt; Darren Mark (San Francisco, CA) Assignee(s): Exelixis, Inc. (South San Francesco, CA) Patent Number: 6,627,746 Date filed: May 26, 1998 Excerpt(s): The present invention relates to C. elegans insulin-like genes and methods for identifying insulin-like genes. The methods provide nucleotide sequences of C. elegans insulin-like genes, amino acid sequences of their encoded proteins, and derivatives (e.g., fragments) and analogs thereof. The invention further relates to fragments (and derivatives and analogs thereof) of insulin-like proteins which comprise one or more domains of an insulin-like protein. Antibodies to an insulin-like protein, and derivatives and analogs thereof, are provided. Methods of production of an insulin-

252 Insulin

like protein (e.g., by recombinant means), and derivatives and analogs thereof, are provided. Methods to identify the biological function of a C. elegans insulin-like gene are provided, including various methods for the functional modification (e.g., overexpression, underexpression, mutation, knock-out) of one gene, or of two or more genes simultaneously. Methods to identify a C. elegans gene which modifies the function of, and/or functions in a downstream pathway from, an insulin-like gene are provided. Citation of references herein shall not be construed as an admission that such references are prior art to the present invention. Insulin-like proteins are a large and widely-distributed group of structurally-related peptide hormones that have pivotal roles in controlling animal growth, development, reproduction, and metabolism (Blundell and Humbel, 1980, "Hormone families: pancreatic hormones and homologous growth factors", Nature 287:781-787). Consequently, the insulin superfamily has become one of the most intensively investigated classes of peptide hormones. Such hormones have a vast array of uses including, for example, clinical applications in human disease, management of fish and livestock, and the control of agriculturally-important animal pests. At least five different subfamilies of insulin-like proteins have been identified in vertebrates, represented by insulin (Steiner et al., 1989, in Endocrinology, DeGroot, ed., Philadelphia, Saunders, pp. 1263-1289), insulin-like growth factor (IGF, previously termed somatomedin) (Humbel, 1990, "Insulin-like growth factors I and II", Eur. J. Biochem. 190:445-462), relaxin (Schwabe and Bullesback, 1994, "Relaxin: structures, functions, promises, and nonevolution", FASEB J. 8:1152-1160), relaxin-like factor (RLF, previously called Leydig cell-specific insulin-like peptide) (Adham al., 1993, "Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells", J. Biol. Chem. 268:26668-26672; Ivell, 1997, "Biology of the relaxin-like factor (RLF)", Reviews of Reproduction 2:133-138), and placentin (also known as early placenta insulin-like peptide, or ELIP) (Chassin et al., 1995, "Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta", Genomics 29:465-470). Web site: http://www.delphion.com/details?pn=US06627746__ •

Particles based on polyamino-acid(s) and methods for preparing same Inventor(s): Brison; Nathan (Millery, FR), Huille; Sylvain (Bordeaux, FR), Nicolas; Florence (Genas, FR), Soula; Gerard (Meyzieu, FR) Assignee(s): Flamel Technologies (Venissieux Cedex, FR) Patent Number: 6,630,171 Date filed: July 6, 2001 Abstract: The invention concerns delivery particles (DP's) for active principles (AP's) based on linear amphiphilic polyamino-acids (PAA's), with.alpha.-peptide chains, capable of being spontaneously formed by contacting PAA's with a liquid medium, preferably with water, wherein the hydrophile part of the PAA's is solubilized more than the hydrophobic parts of said PAA's, such that the latter precipitate while being organised in discrete supra-molecular arrangements, of average size ranging between 0.01 and 20.mu.m, capable of combining with at least an AP and releasing the latter in vivo, in prolonged and controlled manner. The inventive suspension is characterised in that the recurrent amino acids (rAA's) constituting the main chain of PAA's are identical to or different from one another and are glutamic acid and/or aspartic acid and/or their salts; and some of said rAA's bear at least one hydrophobic group, said hydrophobic group, being identical to or different from one another. The invention is useful as

Patents 253

carriers for active principles, in particular pharmaceutical, insulin or for therapeutic uses. Excerpt(s): This application is a 371 of PCT/FR99/02859, filed on Nov. 19, 1999. The field of the present invention is that of Delivery Particles (DPs) which can be used for the administration of active principles (APs). The latter are preferably medicinal products or nutrients for adminstration to an animal or human organism via the oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral, parenteral, etc. route. However, they may also be plantprotection products, such as herbicides, pesticides, insecticides, fungicides, etc. In terms of chemical nature, the APs with which the invention is more particularly, but not exclusively, concerned are, for example, proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligonucleotides and polynucleotides. The present invention relates more specifically to Delivery Particles, advantageously of the submicron type, based on polyamino acids (PAAs). The present invention is directed toward both naked particles per se, and AP vector systems consisting of particles loaded with the AP(s) under consideration. The present invention also relates to aqueous colloidal suspensions comprising these DPs. Web site: http://www.delphion.com/details?pn=US06630171__ •

PI 3-kinase fusion mutants and uses thereof Inventor(s): Harrison; Stephen D. (Berkeley, CA), Kavanaugh; W. Michael (Mill Valley, CA), Klippel; Anke (San Francisco, CA), Williams; Lewis T. (Tiburon, CA) Assignee(s): Chiron Corporation (Emeryville, CA) Patent Number: 6,613,956 Date filed: April 2, 1997 Abstract: Polynucleotide constructs encoding growth factor independent catalytically active membrane targeted PI 3-kinase mutants useful for therapeutic and research purposes are described. In addition, a method for using the polynucleotide constructs to screen for inhibitors of PI 3-kinase, a method for making 3' phosphorylated inositol phospholipids, methods of reducing cell death after trauma, and methods of overcoming insulin resistance are described. Excerpt(s): This invention provides polynucleotide constructs encoding constitutively active membrane-targeted PI 3-kinase mutants, methods for making polynucleotide constructs, an in vivo method for screening for inhibitors of PI 3-kinase using the constructs, use of the polynucleotide constructs to prevent cell death, or to restore insulin responsiveness in type II diabetes, use of the polynucleotide constructs to express PI 3-kinase mutants that generate 3' phosphorylated inositol phospholipids, and use of these phospholipids to prevent cell death. Phosphotidylinositol (PI) 3-kinase, both a phospholipid kinase, and a protein serine/threonine kinase, is implicated in certain oncogenic or mitogenic responses. See Carpenter et al., Mol. Cell. Biol. 13:1657-1665 (1993), Cantley et al., Cell 64:281-302 (1991), Escobedo and Williams, Nature 335:85-87 (1988), and Fantl et al, Cell 69: 413423 (1992). It is an intracellular heterodimer consisting of an 85-kDa regulatory subunit (p85), and a 110-kDa catalytic subunit (p110) that is stimulated by growth factors. See Whitman et al., Nature 332:644-646 (1988). The p85 subunit contains several domains and links the catalytic subunit to activated growth factor receptors. The cDNA for the p110 subunit has recently been cloned and expressed in insect and mammalian systems as described in Hiles et al., Cell 70:419-429 (1992). The

254 Insulin

general structure and function of PI 3-kinase, including analysis of the structure and function of its subunits p85 and p110, are described in Klippel et al., Mol. Cell. Biol. 13:5560-5566 (1993), and in Klippel et al., Mol. Cell. Biol. 14:2675-2685 (1994). The p85 subunit of PI 3-kinase has several domains, including a 200 amino acid region of p85 located between the two SH2 domains. This domain, called the inter-SH2 or iSH2 domain, has been found sufficient to promote interaction with p110 in vivo with activity comparable to that of full-length p85. See Klippel et al., Mol. Cell. Biol. 13:5560-5566 (1993). Additionally, a complex between a 102 amino acid segment of p85 and the p110 subunit has been found to be catalytically active, as described in and Klippel et al., Mol. Cell. Biol. 14:2675-2685 (1994). Web site: http://www.delphion.com/details?pn=US06613956__ •

Platform for the differentiation of cells Inventor(s): Rosenberg; Lawrence (Cote St-Luc, CA) Assignee(s): McGill University (Montreal, CA) Patent Number: 6,638,765 Date filed: August 3, 2001 Abstract: The present invention relates to an in vitro method for islet cell expansion, which comprises the steps of: a) preparing dedifferentiated cells derived from cells in or associated with post-natal islets of Langerhans; b) expanding the dedifferentiated cells; and c) inducing islet cell differentiation the expanded cells of step b) to become insulinproducing cells. Excerpt(s): The invention relates to an in vitro method for islet cell expansion; an in vitro method for producing multi bipolar cells; an in vitro method for stem cell expansion; and a method for the treatment of diabetes mellitus in a patient. Diabetes mellitus has been classified as type I, or insulin-dependent diabetes mellitus (IDDM) and type II, or non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have been subdivided further into (a) nonobese (possibly IDDM in evolution), (b) obese, and (c) maturity onset (in young patients). Among the population with diabetes mellitus, about 20% suffer from IDDM. Diabetes develops either when a diminished insulin output occurs or when a diminished sensitivity to insulin cannot be compensated for by an augmented capacity for insulin secretion. In patients with IDDM, a decrease in insulin secretion is the principal factor in the pathogenesis, whereas in patients with NIDDM, a decrease in insulin sensitivity is the primary factor. The mainstay of diabetes treatment, especially for type I disease, has been the administration of exogenous insulin. Tight glucose control appears to be the key to the prevention of the secondary complications of diabetes. The results of the Diabetes Complications and Control Trial (DCCT), a multicenter randomized trial of 1441 patients with insulin dependent diabetes, indicated that the onset and progression of diabetic retinopathy, nephropathy, and neuropathy could be slowed by intensive insulin therapy (The Diabetes Control and Complication Trial Research Group, N. Engl. J. Med., 1993; 29:977-986). Strict glucose control, however, was associated with a three-fold increase in incidence of severe hypoglycemia, including episodes of seizure and coma. As well, although glycosylated hemoglobin levels decreased in the treatment group, only 5% maintained an average level below 6.05% despite the enormous amount of effort and resources allocated to the support of patients on the intensive regime (The Diabetes Control and Complication Trial Research Group, N. Engl. J. Med., 1993; 29:977-986). The results of the DCCT clearly indicated that intensive control of glucose can significantly reduce (but not

Patents 255

completely protect against) the long-term microvascular complications of diabetes mellitus. Web site: http://www.delphion.com/details?pn=US06638765__ •

Protamine fragment compositions and methods of use Inventor(s): Byun; Youngro (Kwangsan-Ku Kwangju, KR), Yang; Victor C. (Ann Arbor, MI) Assignee(s): The Regents of The University of Michigan (Ann Arbor, MI) Patent Number: 6,624,141 Date filed: November 16, 2000 Abstract: Provided are bioactive, low-toxicity protamine fragments, compositions, combinations, kits and methods of using these components in a variety of embodiments, including neutralizing heparin and reducing post-operative bleeding. Improved protamine fragment-insulin solutions and methods for treating diabetes are also provided. Excerpt(s): The present invention relates generally to the fields of protein biochemistry and medicine. More particularly, it concerns bioactive, low-toxicity fragments of protamine, and a number of different uses of such protamine fragment compositions. Provided are protamine fragments, compositions, combinations and kits and various methods and uses of such fragments, e.g., in the neutralization of heparin and for association with a variety of therapeutic proteins, including insulin. Heparin consists of a heterogeneous mixture of sulfated glycosaminoglycans with a molecular weight ranging from 3,000 to 40,000 daltons. It is made of a repeating unit of D-glucuronic acid and N-acetyl-D-glucosamine residues (Bourin and Lindahl, 1993). The anticoagulant function of heparin was discovered over 70 years ago (Howell, 1922). Heparin exerts its anticoagulant activity primarily via interaction with antithrombin III (Rosenberg, 1987). Antithrombin III (ATIII) is a circulating inhibitor of the serine proteases in the coagulation cascade, acting more particularly on thrombin and factor Xa but also on factors IXa, XIa, and XIIa. It possesses an arginine center that binds to the active serine site of thrombin (and also the other coagulation factors) to form a covalent bond (Griffith, 1983). Normally this reaction proceeds rather slowly. Binding of heparin to ATIII, however, induces a conformational change of ATIII, rendering the arginine center more accessible to thrombin interaction, and producing a 1000-fold acceleration of the inhibitory effect (Rosenberg, 1987). The binding of heparin to ATIII involves a unique pentasaccharide sequence containing a 3-O-sulfated glucosamine residue (Choay et al., 1981), and entails interaction between specific lysine residues on ATIII and sulfate and carboxylate groups in heparin (Choay et al., 1981; Rosenberg et al., 1979). Web site: http://www.delphion.com/details?pn=US06624141__

256 Insulin

•

Purification and stabilization of peptide and protein pharmaceutical agents Inventor(s): Steiner; Solomon S. (Mount Kisco, NY), Sulner; Joseph W. (Paramus, NJ), Woods; Rodney J. (New Hampton, NY) Assignee(s): MannKind Corporation (Danbury, CT) Patent Number: 6,652,885 Date filed: August 20, 2002 Abstract: Methods are provided for purifying peptides and proteins by incorporating the peptide or protein into a diketopiperazine or competitive complexing agent to facilitate removal one or more impurities, i.e. undesirable components, from the peptide or protein. In a preferred embodiment, a peptide, such as insulin, containing one or more impurities, e.g., zinc ions, is entrapped in diketopiperazine to form a precipitate of peptide/diketopiperazine/impurity, which is then washed with a solvent for the impurity to be removed, which is a nonsolvent for the diketopiperazine and a nonsolvent for the peptide. Formulations and methods also are provided for the improved transport of active agents across biological membranes, resulting for example in a rapid increase in blood agent concentration. The formulations include microparticles formed of (i) the active agent, which may be charged or neutral, and (ii) a transport enhancer that masks the charge of the agent and/or that forms hydrogen bonds with the target biological membrane in order to facilitate transport. In a preferred embodiment, insulin is administered via the pulmonary delivery of microparticles comprising fumaryl diketopiperazine and insulin in its biologically active form. The charge on the insulin molecule is masked by hydrogen bonding it to the diketopiperazine, thereby enabling the insulin to pass through the target membrane. This method of delivering insulin results in a rapid increase in blood insulin concentration that is comparable to the increase resulting from intravenous delivery. Excerpt(s): The present invention is generally in the field of pharmaceutical formulations, and more particularly related to methods and compositions for purifying and stabilizing peptides and proteins, such as insulin, which are used in pharmaceutical applications. In a normal person, the.beta.-cells of the pancreatic islets of Langerhans produce insulin, required by the body for glucose metabolism, in response to an increase in blood glucose concentration. The insulin metabolizes incoming glucose and temporarily stops the liver's conversion of glycogen and lipids to glucose thereby allowing the body to support metabolic activity between meals. The Type I diabetic, however, has a reduced ability or absolute inability to produce insulin due to.beta.-cell destruction and needs to replace the insulin via daily injections or an insulin pump. More common than Type I diabetes, though, is Type II diabetes, which is characterized by insulin resistance and increasingly impaired pancreatic.beta.-cell function. Type II diabetics may still produce insulin, but they may also require insulin replacement therapy. Type II diabetics typically exhibit a delayed response to increases in blood glucose levels. While normal persons usually release insulin within 2-3 minutes following the consumption of food, Type II diabetics may not secrete endogenous insulin for several hours after consumption. As a result, endogenous glucose production continues after consumption (Pfeiffer, Am. J. Med., 70:579-88 (1981)), and the patient experiences hyperglycemia due to elevated blood glucose levels. Web site: http://www.delphion.com/details?pn=US06652885__

Patents 257

•

Reusable medication delivery device Inventor(s): Douglas; Joel (Los Altos Hills, CA), Hugo; Robert (Gilroy, CA), Ramirez; John (Sunnyvale, CA) Assignee(s): Sterling Medivations, Inc. (Norcross, GA) Patent Number: 6,641,566 Date filed: June 24, 2002 Abstract: A medication injection or delivery system is provided for injecting fluids such as insulin within body tissue. The device includes a housing, a flexible shaft movably mounted within the housing, and a dose setting mechanism for controlling the movement of the shaft with respect to a fluid-containing cartridge removably positioned within or mounted to the housing. The flexible shaft, according to exemplary embodiments, includes a plunger and a flexible cable connected to the dose setting mechanism. The plunger and dose setting mechanism are connected together by the flexible shaft. The dose setting mechanism, in one aspect of the invention, includes a screw, a locking mechanism, and a nut assembly connected to the flexible shaft. The dose setting mechanism is used to set the dosage and prime the catheter. The plunger retracts into a recess to permit a new cartridge to be installed quickly. Excerpt(s): The present invention relates to devices for delivering a predetermined amount of a substance to a patient, and more particularly to a manual medication delivery device. The present invention also relates to methods of use and kits including such devices. There are many medical conditions that require the administration of liquid medicaments transcutaneously (through the skin) for prolonged periods. Diabetes, for example, may be controlled by daily, or more frequent, injections of insulin. The ability to administer numerous small dosages of insulin has been proven to be the best way to insure tight glucose control for a patient. The National Institutes of Health (NIH) conducted a long-term study of people with diabetes known as the Diabetes Complications and Control Trial (DCCT) were it was determined that the proper management of diabetes requires 4 or more injections of insulin per day. However, current devices either are not convenient or easy to use by patients. Syringes and insulin pens all require the patients to inject themselves and do not provide a convenient or discreet mechanism to accomplish medication delivery. Since transcutaneous injections are painful and troublesome, and since each injection represents a possibility for infection, injections are spaced at intervals as far apart as possible, resulting in peak and valley concentrations of the medicament in the bloodstream or at the site in the body requiring the medicament, the peak concentrations occurring shortly after the administration of the medicament and the low, or valley, concentrations occurring shortly before the administration of the next injection. This method of administration exposes the patient to the possibility of overdose at peak levels and underdose at valley levels, but was nevertheless the standard method for many years in the absence of a better alternative. Web site: http://www.delphion.com/details?pn=US06641566__

258 Insulin

•

Serum free medium for chondrocyte cells Inventor(s): Cancedda; Ranieri (Genoa, IT), Dozin; Beatrice (Rapallo, IT) Assignee(s): Consorzio per la Gestione del Centro di Biotechnologie Avanzate (Genoa, IT), Istituto Nazionale per la Ricerca Sul Cancro (Genoa, IT) Patent Number: 6,617,159 Date filed: June 11, 2001 Abstract: Serum free media for growth and proliferation of chondrocytes and mesenchymal stem cells in culture are provided. A serum free medium for growth of chondrocytes includes a serum free composition comprising FGF-2, linoleic acid, ascorbic acid, B-mercaptoethanol, transferrin and dexamethasone. Further the composition comprises EGF, PDGFbb, insulin and albumin. A method for growing chondrocytes in a serum free medium comprising the composition is also provided. Also provided for mesenchymal stem cell growth, is a serum free medium which includes a composition comprising FGF-2, LIF, SCF, pantotenate, biotin and selenium and method, therefore. Excerpt(s): Bone and cartilage transplantation is an absolute need in reconstruction of bone and cartilage segments in plastic surgery, traumatic surgery or after the removal of neoplastic lesions, etc. Typically, material of human (autologous, from donors or from cadavers) or animal origin has been used for this purpose. Given the increased demand from clinicians for transplant tissues, the increased need for microbial safety in tissue transplantation, the advances in cell biology, cell differentiation and tissue engineering, the concept of rebuilding tissues from autologous or allogeneic cells expanded in vitro has become a growing field in the world of biomedical sciences. Cellular sources for skeletal repair include chondrocytes and cells committed to the chondrocyte lineage, and mesenchymal stem cells, the former specific for cartilage, the latter multipotential and therefore having the potential to be used to replace bone, cartilage and other tissues. Mesenchymal stem cells (MSCs) are found in bone marrow as well as in blood, dermis and periosteum. Although these cells are normally present at very low frequencies in bone marrow, these cells can be isolated purified and culturally expanded, for example, as described in U.S. Pat. No. 5,486,359. Typically, the ill vitro expansion of chondrocytes and MSCs takes place in culture medium supplemented with bovine serum or optimally with autologous serum from the patient. However, the presence of animal or autologous serum in chondrocyte and MSC cultures has certain disadvantages and limitations in view of the potential therapeutical applications of these cultures. Web site: http://www.delphion.com/details?pn=US06617159__

•

Serum-free cell growth medium Inventor(s): Erlacher; Ludwig (Vienna, AT), Luyten; Frank P. (Kraainem, BE) Assignee(s): The United States of America as represented by the Department of Health and (Washington, DC) Patent Number: 6,617,161 Date filed: May 9, 2001 Abstract: A chemically defined-serum free growth medium for the in vitro and ex vivo of cells and cell lines. The medium consists of about a one to one ratio (v/v) of two basal growth media containing.alpha.-ketoglutarate, insulin, transferrin, selenium, bovine

Patents 259

serum albumin, linoleic acid, ceruloplasmin, cholesterol, phosphatidylethanolamine,.alpha.-tocopherol acid succinate, reduced glutathione, taurine, triiodothyronine, hydrocortisone, parathyroid hormone, L-ascorbic acid 2-sulfate,.beta.glycerophosphate, PDGF, EGF and FGF. Chondrocytes, when cultured in this medium in the presence of a cartilage derived morphogenetic protein or bone morphogenetic protein, retain their cartilaginous phenotype. Excerpt(s): The present invention relates to a cell growth medium. More specifically, the invention relates to a chemically defined serum-free growth medium useful for the expansion of primary cells or cell lines in culture. Culturing of mammalian cells is an essential technique for research into cellular processes, production of recombinant therapeutic proteins, and generation of expanded cells for transplantation purposes. Cell culture studies have led to the determination of numerous metabolic processes and the identification of growth factors, hormones and their receptors (Bio Techniques, 5:534542, 1987). The composition of media used to culture cells is of paramount importance because of its influence on cell survival and cell response to various effectors. Conventional cell culture media comprise basal nutrient media supplemented with serum from various sources, most often fetal bovine serum, horse serum or human serum. However, the use of serum is undesirable for several reasons. Growth media containing serum may vary in composition, hormone content, and contaminants, thereby introducing extraneous factors and/or infections agents into the culture system (Bio Technology, 11:49-53, 1993; Pharm. Technol., 48:56, 1987). In addition, serum is expensive, impractical for large-scale production of therapeutics. Further, variance between serum lots and laboratory protocols is also a problem. Recent concerns by the FDA, the European community, and others about serum quality, contamination (i.e., bovine spongiform encephalopathy, bovine immunodeficiency virus), and increased demand have generated significant interest in the development and utility of serum-free growth media. Web site: http://www.delphion.com/details?pn=US06617161__ •

Single-chain insulin analog and a polynucleotide sequence encoding the analog Inventor(s): Kim; Kyung Sup (Yongdeungpogu Yeoyeedodong Samik, Apt. B-202, Seoul, KR), Kim; Su-Jin (Dukyanggu Haengsindong 938 Haibit 1819-1304, Goyangsi, KR), Lee; Hyun Chul (Seodaemungu Hongeundong 268, Dongdo-academyhouse A-402, Seoul, KR), Shin; Hang-Cheol (Seochogu Wonjidong 401-37, Seoul, KR), Yoon; Ji-Won (206 Edgeview Drive, N.W., Calgary, Alberta, CA T3A 4X5) Assignee(s): none reported Patent Number: 6,630,348 Date filed: November 7, 2000 Abstract: The subject matter of the invention is directed to a single-chain insulin analog that is used to treat diabetes by gene therapy methods. Excerpt(s): The present invention relates to a method of introducing at least one singlechain insulin analog protein or a gene encoding a single-chain insulin analog (SIA) into at least one mammalian tissue for use in treating diabetes in the mammalian host. The present invention also relates to the single-chain insulin analog and a recombinant vector construct comprising the gene encoding SIA. The cure of diabetes has long been sought using several different approaches, including islet transplantation, regeneration of.beta. cells and insulin gene therapy (Levine, F. & Leibowitz, G. Towards gene

260 Insulin

therapy of diabetes mellitus. Mol. Med. Today 5, 165-171 (1999)). However, the permanent remission of type 1 diabetes has not yet been satisfactorily achieved. There remains a very real and substantial need for a method of introducing at least one gene encoding a single-chain insulin analog to at least one cell of a mammalian host in vitro or in vivo, for use in treating the mammalian host suffering from diabetes. Web site: http://www.delphion.com/details?pn=US06630348__ •

System and method for treating kidney diseases in diabetic and non-diabetic patients Inventor(s): Aoki; Thomas T. (1021 El Sur Way, Sacramento, CA 95825) Assignee(s): none reported Patent Number: 6,613,342 Date filed: June 15, 2001 Abstract: The present invention is a system and method capable of improving the entire metabolic process and through its multiplicity of effects on neurovascular reactivity, intraglomerular pressure and hemodynamics, arresting the progression of overt diabetic nephropathy, improving intraglomerular hemodynamics, and thus arresting the progression of diabetic nephropathy and therefore reducing the risk of development of End Stage Renal Disease. The current system and method is for the treatment of kidney disease using insulin pulses to a patient utilizing Chronic Intermittent Intravenous Insulin Therapy to achieve the slowing, stopping or reversing of kidney disease in both diabetic and non-diabetic patient. Excerpt(s): This invention relates to the treatment of kidney disease in diabetic and nondiabetic patients. More specifically, the invention relates to a system and method for treating kidney disease in diabetic and non-diabetic patients with Chronic Intermittent Intravenous Insulin Therapy. Diabetic kidney disease (nephropathy) develops in 35 to 40% of patients with type 1 diabetes mellitus (DM) and in 10 to 60% of patients with type 2 DM depending upon the ethnic pool being studied. It is the most common cause of End-Stage Renal Disease (ESRD) in the United States. Experts generally have assumed that diabetic nephropathy is the result of hyperglycemia, whether alone or in combination with other factors, such as hypertension and genetic susceptibility to kidney disease. Two major recent clinical trials involving patients with type 1 DM (Diabetes Control and Complication Trial [DCCT]) and type 2 DM (United Kingdom Prospective Diabetes Study [UKPDS]) have demonstrated that improved glycemic control reduces the onset and the progression of early diabetic nephropathy to overt nephropathy in patients recently diagnosed with diabetes mellitus (DM) thereby giving additional credence to the hypothesis that a lack of glycemic control is the primary cause. Both of theses studies used recently diagnosed patients some of whom, although well controlled, went on to develop kidney disease. Since the DCCT and UKPDS studies demonstrated that near normalization of blood glucose level did not always result in a delay of the onset or progression of diabetic nephropathy, the hypothesis that euglycemia is the means for addressing this disease, is made suspect. Once nephropathy has become clinically overt (that is, macroalbuminuria and decreased glomerular filtration rate are detected), the degree of glycemic control is shown to have lost its importance as a factor. This provides additional evidence to refute the claim that glycemic control is the primary factor to be addressed in kidney disease, and that other mechanisms have greater overall influence. Indeed, most patients with DM and proteinuria eventually will progress to ESRD or premature death from cardiovascular complications. In such patients, with no medical intervention, the glomerular filtration

Patents 261

rate decreases an average of 1 ml/min per month, a deterioration that leads to ESRD in a mean period of 7 years. Once overt persistent proteinuria is established, no known strategy exists that can stop or reverse the progression to ESRD. Appropriate antihypertensive therapy has been shown to significantly reduce renal and possibly cardiovascular mortality in proteinuric type 1 DM patients, as well as retard the rate of decline of glomerular filtration rate in some patients with impaired renal function (Lewis A J et al, N Engl J Med 1993,329:1456-62). Thus, the standard of care for patients with diabetic nephropathy is intensive glycemic control and normalization of the blood pressure using primarily angiotensin converting enzyme inhibitors. Web site: http://www.delphion.com/details?pn=US06613342__ •

Transcription factor islet-brain 1 (IB1) Inventor(s): Bonny; Christophe (Geneva, CH), Waeber; Gerard (Chemin de la Rueyre 59, Jouxtens, CH CH-1008) Assignee(s): Nicod; Pascal (CH), Waeber; Gerard (CH) Patent Number: 6,620,914 Date filed: December 22, 1999 Abstract: The identification and characterisation of human and rat Islet-Brain 1 (IB1) is disclosed, a transcriptional activator that is involved in the control of the GLUT2 and insulin genes by interacting with homologous cis-regulatory elements of the GLUT2 and insulin promoters. The rat IB1 cDNA encodes a 714 amino acid protein and the human IB1 cDNA a 711 amino acid protein. The use of IB1 polypeptides, nucleic acid, agonists and antagonists in the treatment or diagnosis of diabetes, neurological diseases such as dementia and/or parkinsonism, the inhibition/promotion of apoptosis and cancer is disclosed. Excerpt(s): The present invention relates to identification and characterisation of IsletBrain 1 (IB1), a transcriptional activator that is involved in the control of the GLUT2 and insulin genes by interacting with homologous cis-regulatory elements of the GLUT2 and insulin promoters, and to materials and methods deriving from this work. In particular, the present invention relates to the uses of IB1 nucleic acid, IB1 polypeptides, IB1 antagonists and antibodies in the diagnosis, and prophylactic and therapeutic treatment of conditions such as diabetes, neurological diseases such as dementia and/or parkinsonism, cancer and in the promotion or inhibition of apoptosis. The GLUT2 facilitated glucose transporter isoform is a membrane protein present in the pancreatic.beta.-insulin-secreting cells, the basolateral membrane of intestinal and kidney absorptive cells, in hepatocytes and in a subset of neurons (21,31,44). In these cells, GLUT2 catalyzes the transepithelial transport of glucose. In pancreatic islets, GLUT2 allows a rapid equilibration of glucose between the extracellular space and the interior of the cells and it may play a crucial role in the glucose signalling mechanism leading to insulin secretion (43). However, the relative importance of GLUT2 in the sensing of the.beta.-pancreatic cells to glucose remains debated. In human.beta.-cells, the level of expression of GLUT2 is low and the intracellular glucokinase activity seems to be the rate-limiting step in the glycolytic pathway (5,11). On the other hand, insulinoma cells that had lost their normal glucose responsiveness have low GLUT2 content, but some glucose sensitivity may be recovered after reintroducing GLUT2 expression through stable transfection of these cells (10,16). Furthermore, transgenic mice that express GLUT2 antisense RNAs driven by the insulin promoter led to an 80% reduction in GLUT2 which was paralleled by a decreased glucose-induced insulin secretory

262 Insulin

response and by the onset of diabetes (48). These observations are critical since several experimental models of diabetes have shown that GLUT2 expression is dramatically reduced specifically in the pancreatic.beta.-cells, and that this mechanism could participate to the onset of the disease (18,29,30,32,45-47). Therefore, while GLUT2 levels are unchanged or even upregulated in several tissues such as the liver and the intestine during the hyperglycemic conditions observed in diabetes, the same gene undergoes a drastic dysregulation only in the pancreatic islets. A fragment of the murine GLUT2 promoter has been cloned and shown to be glucose-responsive when transfected into differentiated insulin-producing cells or into hepatocytes (35,36,52). Important cisregulatory sequences were identified within this promoter region including a functionally responsive PDX-1 element, a cyclic AMP responsive element, and three ciselements termed GTI, GTII and GTIII (3,36,53). The presence of GTI, II and III are both sufficient and necessary to confer pancreatic-specific expression to a reporter gene in vitro or in vivo, using a transgenic mice approach (3,51). GTI and GTIII have been previously shown to bind distinct, but ubiquitously expressed trans-acting factors. Web site: http://www.delphion.com/details?pn=US06620914__

Patent Applications on Insulin As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to insulin: •

ANTIDIABETIC AGENTS Inventor(s): Bigge, Christopher F.; (Ann Arbor, MI), Schaum, Robert P.; (Ann Arbor, MI) Correspondence: Heidi M. Berven; Warner-lambert Company, Llc; 2800 Plymouth Road; Ann Arbor; MI; 48105; US Patent Application Number: 20030220381 Date filed: March 17, 2003 Abstract: Compounds of formula I: 1wherein X, Y, B, E, J, K, L, Z, and R.sub.9-R.sub.12 have any of the meanings described herein, their pharmaceutically acceptable salts, lower blood glucose levels and are useful for treating diseases in mammals such as NonInsulin Dependent Diabetes Mellitus. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) and intermediates useful for preparing compounds of formula I. Excerpt(s): This application claims benefit of priority from U.S. Provisional Application Serial No. 60/369,787 filed on Apr. 3, 2002. The present invention relates to compounds that are useful as antidiabetic agents. Type II diabetes, or non-insulin dependent diabetes (NIDDM) is a significant healthcare problem whose incidence is on the rise. Between 1990 and 1998, the prevalence of NIDDM in the United States increased by 33 percent, to about 13 million persons. An additional 5 million persons are presumed to have undiagnosed NIDDM, while another 14 million persons have impaired glucose tolerance. Direct medical costs associated with diabetes were $44 billion in 1997, due mainly to hyperglycemia-related diabetic complications, including diabetic angiopathy,

10

This has been a common practice outside the United States prior to December 2000.

Patents 263

atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation, and glaucoma. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors Inventor(s): Du Bois, Daisy Joe; (Palo Alto, CA) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030195361 Date filed: February 14, 2003 Abstract: This invention relates to compounds of Formula I 1or stereoisomers, pharmaceutically acceptable salts or prod rugs thereof or a pharmaceutically acceptable salts of the prodrugs. This invention also relates to pharmaceutical compositions comprising a compound of Formula I, and to methods of treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia. Excerpt(s): This invention relates to bicyclic pyrrolyl amides and pharmaceutical compositions comprising bicyclic pyrrolyl amides. This invention also relates to the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia, using the bicyclic pyrrolyl amides. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

264 Insulin

•

Bile secretagogues Inventor(s): Kawamura, Ikuo; (Osaka, JP), Manda, Toshitaka; (Osaka, JP), Ota, Mariko; (Hyogo, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030220269 Date filed: May 27, 2003 Abstract: The invention provides a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis each comprising insulin-like growth factor I or an analog thereof as well as a method of promoting secretion of bile which comprises administering insulin-like growth factor I or an analog thereof, a method of promoting secretion of bile acids, and a method for therapy of cholestasis in mammals. Excerpt(s): This invention relates to a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis. More particularly, the invention relates to a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis each comprising insulin-like growth factor (I) or an analog thereof and to a method of promoting secretion of bile, a method of promoting secretion of bile acids, and a method for therapy of cholestasis, each comprising administering insulin-like growth factor I or an analog thereof to mammals. Cholestasis is a symptom of various diseases of the liver. Its etiology, roughly classified, may be iatrogenic (drug-related), viral or congenital. As therapeutic drugs for cholestasis, adrenocortical hormones and ursodeoxycholic acid have heretofore been chiefly used, but adrenocortical hormones have the disadvantage of side effects, while the effect of ursodeoxycholic acid is not fully satisfactory. The inventors of this invention made intensive investigations and found that insulin-like growth factor I (IGF-I) has a potent choleretic action and have developed this instant invention. To be an additional surprise, whereas adrenocortical hormones, such as prednisolone, and ursodeoxycholic acid, all in routine use, exert choleretic actions, IGF-I has both choleretic and bile acid secretion-promoting actions and is expected to provide a new selective therapeutic modality. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Chimeric pancreas Inventor(s): Hammerman, Marc R.; (St. Louis, MO) Correspondence: Michael T. Marrah; Sonnenschein Nath & Rosenthal; P.O. Box #061080; Wacker Drive Station, Sears Tower; Chicago; IL; 60606-1080; US Patent Application Number: 20030198628 Date filed: March 24, 2003 Abstract: Novel methods, tissues and compositions for increasing the pancreatic mass of a mammalian recipient including harvesting immature pancreatic tissue from a mammalian donor and transplanting said tissue into the peritoneal cavity of a mammalian recipient under conditions that allow the pancreatic tissue to become vascularized and mature, thereby developing a functioning chimeric, endocrine pancreas that produces at least insulin in the recipient. The invention also includes

Patents 265

mammalian immature pancreatic tissue adapted for transplantation into the peritoneal cavity of a mammalian recipient for increasing the pancreatic mass of the mammalian recipient as well as methods and compositions for treatment of the pancreatic tissue, recipient immunosuppression and recipient co-stimulatory blockade. Excerpt(s): This application claims the benefit of U.S. provisional application Serial No. 60/367,181, filed Mar. 25, 2002 and incorporated herein as if restated here in full. The present invention relates to the field of biotechnology, in particular, methods, tissues and compositions for increasing the pancreatic mass of a mammalian recipient. Idiopathic or primary diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized in its fully expressed form by an absolute or relative insulin deficiency, fasting hyperglycemia, glycosuria, and a striking tendency toward development of atherosclerosis, microangiopathy, nephropathy, and neuropathy. Underutilization of glucose is characteristic of all diabetic patients, but only some have a clearly defined severe insulin deficiency resulting from a loss of beta cells. The large remainder of diabetic patients suffers from some impairment of insulin secretory response associated with a marked resistance to insulin in the peripheral tissues. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Combination therapy using a dual PPAR-a/PPAR-y activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders Inventor(s): Bury, Paul Stanley; (Kobenhavn, DK), Jeppesen, Lone; (Virum, DK), Mogensen, John Patrick; (Herlev, DK), Pettersson, Ingrid; (Frederiksberg, DK), Sauerberg, Per; (Farum, DK) Correspondence: Reza Green, ESQ.; Novo Nordisk Pharmaceuticals, INC.; 100 College Road West; Princeton; NJ; 08540; US Patent Application Number: 20030199451 Date filed: May 20, 2003 Abstract: The present invention relates to a pharmaceutical composition comprising a dual Peroxisome Proliferator-Activated Receptor-alpha/Peroxisome ProliferatorActivated Receptor-gama activator (PPAR-.alpha./PPAR-.gamma.- ) and a Glucagon Like Peptide-1 (GLP-1) derivative for treating, preventing and reducing the risk of developing Type 2 diabetes, insulin resistance, dyslipidemia, obesity, hypertension and other related diseases and disorders. Excerpt(s): This application is a continuation of application Ser. No. 09/771,217, having a filing date of Jan. 26, 2001, now issued U.S. Pat. No. ______, the contents of which are herein incorporated by reference in its entirety. The present invention relates to a pharmaceutical composition comprising a dual Peroxisome Proliferator-Activated Receptor-alpha/Peroxisome Proliferator-Activated Receptor-gama activator (PPAR.alpha./PPAR-.gamma.) and a Glucagon Like Peptide-1 (GLP-1) derivative for treating, preventing and reducing the risk of developing Type 2 diabetes, insulin resistance, dyslipidemia, obesity, hypertension and other related diseases and disorders. Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the `deadly quartet` category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

266 Insulin

•

Commercial production of insulin and insulin-like proteins in plants Inventor(s): Howard, John; (College Station, TX), Streatfield, Stephen; (Bryan, TX) Correspondence: Patricia A. Sweeney; 1835 Pleasant ST.; West Des Moines; IA; 50265; US Patent Application Number: 20030200566 Date filed: March 7, 2003 Abstract: Plants are engineered to express proinsulin or insulin. The plants can be used as a source of the protein for a variety of purposes. Plant tissue can be orally administered to animals to replace the necessity of injection of insulin. Alternatively, the protein can be extracted from plant tissue and delivered to animals. Plant produced proteins can also provide a less expensive and more readily available source of the protein as reagents or in other experimentation involving insulin proteins. Excerpt(s): This application claims priority to previously filed and co-pending application U.S. Ser. No. 60/362,874; this application and all references cited herein are incorporated herein by reference. Over the past decade, transgenic plants have been successfully used to express a variety of proteins in plants, including genes from bacterial and viral pathogens. Numerous genes have been cloned into a variety of transgenic plants including many enzymes that have demonstrated the same enzymatic activity as their authentic counterparts. See, for example, expression of avidin in plants, U.S. Pat. No. 5,767,379; aprotinin expressed in plants, U.S. Pat. No. 5,824,870 and proteases expressed in plants, U.S. Pat. No. 6,087,558.; Hood, E. E., D. R. Withcher, S. Maddock, T. Meyer, C. B. M. Baszczynski, M. Bailey, P. Flynn, J. Register, L. Marshal, D. Bond, E. Kulisek, A. Kusnadi, R. Evangelista, Z. Nikolov, C. Wooge, R. J. Mehigh, R. Hernan, W. K. Kappel, D. Ritland, P. C. Li, and J. A. Howard, 1997, Commercial production of avidin from transgenic maize: characterization of transformant, production, processing, extraction and purification. Molecular Breeding 3:291-306; Pen, J., L. Molendijk, W. J. Quax, P. C. Sijmons, A. J. van Ooyen, P. J. van den Elzen, K. Rietveld, and A. Hoekema, 1992, Production of active Bacillus licheniformis.alpha.amylase in tobacco and its application in starch liquefaction. Biotechnology 10:292-296; Trudel, J., C. Potvin, and A. Asselin 1992 Expression of active hen egg white lysozyme in transgenic tobacco. Plant Sci. 87:55-67. Many additional genes have been expressed in plants solely for their immunogenic potential, including viral proteins (U.S. Pat. No.6,136,320; Mason, H. S., J. M. Ball, J. -J. Shi, X. Jiang, M. K. Estes, and C. J. Arntzen. 1996. Expression of Norwalk virus capsid protein in transgenic tobacco and potato and its oral immunogenicity in mice. Proc. Natl. Acad. Sci. USA 93:5335-5340; Wigdorovitz, supra; Kapusta, et al, supra; McGarvey, P. B., J. Hammond, M. M. Dienelt, D. C. Hooper, Z. F. Fu, B. Dietzschold, H. Koprowski, and F. H. Michaels. 1995. Expression of the rabies virus glycoprotein in transgenic tomatoes. Biotechnology 13:1484-1487; Thanavala, Y., Y. -F. Yang, P. Lyons, H. S. Mason, and C. J. Arntzen. 1995. Immunogenicity of transgenic plant-derived hepatitis B surface antigen. Proc. Natl. Acad. Sci. USA 92:3358-3361) and subunits of bacterial toxins (Arakawa, T., D. K. X. Chong, J. L. Merritt, W. H. R. Langridge. 1997. Expression of cholera toxin B subunit oligomers in transgenic potato plants. Transgenic Res. 6:403-413; Arakawa, T., J. Yu, and W. H. Langridge. 1999. Food plant-delivered cholera toxin B subunit for vaccination and immunotolerization. Adv. Exp. Med. Biol. 464:161-178; Haq, T. A., H. S. Mason, J. D. Clements, and C. J. Arntzen. 1995. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science 268:714-716). Animal and human immunization studies have demonstrated the effectiveness of many plant derived recombinant antigens in stimulating the immune system. The production of antigen-

Patents 267

specific antibodies and protection against subsequent toxin or pathogen challenge demonstrates the feasibility of plant derived-antigens for immunologic use. For example, the resulting peptides induced an immunogenic response in mice (Mason, H. S., T. A. Haq, J. D. Clements, C. J. Arntzen. 1998. Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine 16:1336-1343; Wigdorovitz, A., C. Carrillo, M. J. Dus Santos, K. Trono, A. Peralta, M. C. Gomez, R. D. Rios, P. M. Franzone, A. M. Sadir, J. M. Escribano, M. V. Borca. 1999. Induction of a protective antibody response to foot and mouth disease virus in mice following oral or parenteral immunization with alfalfa transgenic plants expressing the viral structural protein VP1. Virology 255:347-353), and humans (Kapusta, J., M. Modelska, M. Figlerowicz, T. Pniewski, M. Letellier, O. Lisowa, V. Yusibov, H. Koprowski, A. Plucienniczak, A. B. Legocki. 1999. A plant-derived edible vaccine against hepatitis B virus. FASEB J. 13:1796-1799) comparable to that of the original pathogen. Characterization studies of these engineered immunogens have proven the ability of plants to express, fold and modify proteins in a manner that is consistent with the native source. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and method for preparation of an oral dual controlled release formulation of a protein and inhibitor Inventor(s): Agarwal, Vikas; (Plymouth, MN), Khan, Mansoor A.; (Amarillo, TX) Correspondence: Cox & Smith Incorporated; Suite 1800; 112 East Pecan Street; San Antonio; TX; 782051536 Patent Application Number: 20030220254 Date filed: March 31, 2003 Abstract: The application discloses a composition and method for an oral dual controlled release formulation of a protein and absorption modifier. The coprecipitation technique for preparation of microcapsules of insulin as a model protein was evaluated and dissolution stability experiments in the presence of trypsin and.alpha.chymotrypsin using chicken and duck ovomucoids as absorption modifiers were performed. The novel formulation improves the bioavailability of the protein with ovomucoids, while conserving the protein structure even after formulation and processing. An optimization design was used to evaluate critical process variables including the rate of addition of polymeric solution, compression pressure, and volume of water with respect to polymeric solution. The novel formulation incorporates controlled release characteristics of both protein and inhibitor to enhance protein stability and bioavailability with less potential for inhibitor concentration-related toxicity. The novel formulation utilizes an aqueous polymer having a pH sensitive solubility for targeted protein release. Excerpt(s): This application claims the benefit under Title 35 United States Code.sctn.119(e) of U.S. Provisional Application No. 60/368,489 filed Mar. 29, 2002. The present invention relates, in general, to formulations for the oral delivery of proteins. More specifically, the present invention is directed to an oral dual controlled release formulation of a protein and inhibitor and to methods of preparing and using these compounds. The advent of recombinant DNA technology and proteomics has spawned tremendous interest and rapid development of research in therapeutic polypeptides and proteins. At this time, however, the common route of administration of these therapeutics is still through injections. In the past few decades, there has been great

268 Insulin

interest in the development of non-invasive routes for delivery of proteins and polypeptides. Among the non-invasive routes, the oral route for delivery of proteins is most desirable in terms of convenience and ease of administration. However, ingested proteins and polypeptides are generally broken down into amino acids by enzymes located in various regions of the gastrointestinal (GI) tract. These amino acids are then absorbed by the epithelium of the GI tract. Because the amino acids do not retain the original biological activity of the protein or polypeptide, their therapeutic efficacy is often lost. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Development and use of human pancreatic cell lines Inventor(s): Beattie, Gillian M.; (Poway, CA), Hayek, Alberto; (La Jolla, CA), Levine, Fred; (Del Mar, CA), Wang, Sijian; (Dallas, TX) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030202967 Date filed: March 27, 2003 Abstract: This invention relates to cell lines, particularly mammalian cell lines, established by transforming the cells with vectors, preferably retroviral vectors, containing two or more oncogenes under the control of one or more inducible promoters and/or genetic elements. Also within the scope of the invention are human cell lines with extended in vitro lifespan, transformed by vectors containing one or more oncogenes under the control of one or more, preferably exogenous, inducible promoters and/or genetic elements. The vectors may additionally contain gene(s) encoding for desired gene product(s). Also disclosed are insulin producing human pancreatic cell lines useful for transplantation into human diabetic patients. Excerpt(s): This is a continuation-in-part patent application of U.S. patent application Ser. No. 08/509,121 filed on Jul. 31, 1995 which was a continuation-in-part patent application of U.S. patent application Ser. No. 08/386,897 filed on Feb. 10, 1995, both of which are incorporated by reference in their entirety. This invention relates to genetically engineered cell lines and cell transplantation therapy. In particular, it relates to oncogene-transformed cell lines useful for transplantation. Insulin is synthesized, processed and secreted by pancreatic.beta. cells, the major endocrine cell type in the islets of Langerhans that are distributed throughout the pancreas. Pancreatic.beta. cells secrete insulin in response to an increase in extracellular glucose concentration. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 269

•

Enzyme inhibitors Inventor(s): Cascon, Mercedes Alonso; (Madrid, ES), Diaz, Isabel Dorronsoro; (Madrid, ES), Gil, Ana Martinez; (Madrid, ES), Jurado, Francisco Wandosell; (Madrid, ES), Morera, Ana Castro; (Madrid, ES), Munoz, Francisco Jose Moreno; (Madrid, ES), Perez, Maria Concepcion Martin; (Madrid, ES) Correspondence: Y. Rocky Tsao; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030195238 Date filed: November 8, 2002 Abstract: Compounds of general formula (I): 1where A, E, G, X, Y and the bond - - - take various meanings are of use in the preparation of a pharmaceutical formulation, for example in the treatment of a disease in which GSK-3 is involved, including Alzheimer's disease or the non-dependent insulin diabetes mellitus, or hyperproliferative disease such as cancer, displasias or metaplasias of tissue, psoriasis, arteriosclerosis or restenosis. Excerpt(s): The present invention relates to enzyme inhibitors, and more particularly to heterocyclic inhibitors of glycogen synthase kinase 3.beta., GSK-3. Alzheimer's disease (AD) is a neurodegenerative process characterised by cognitive disorders associated with a progressive deterioration of the cholinergic function, and neuropathological lesions as senile plaques, formed by the fibrillary.beta.-amyloid, and neurofibrillary tangles, bundles of paired helical filaments. Generally speaking, AD is restricted to groups aged 60 years or more and is the most common cause of dementia in the elderly population. Today, AD affects 23 million people worldwide. As longevity increases, it is estimated that by the year 2050 the number of cases of AD will more than triplicate [Amaduci, L.; Fratiglioni, L. "Epidemiology of AD: Impact on the treatment", in Alzheimer Disease: Therapeutic Strategies, E. Giacobini and R. Becker, Eds., Birhauser, EEUU, 1994, pp. 8]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Heterocyclic containing biphenyl aP2 inhibitors and method Inventor(s): Magnin, David R.; (Hamilton, NJ), Robl, Jeffrey A.; (Newtown, PA) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030199563 Date filed: December 17, 2002 Abstract: aP2 inhibiting compounds are provided having the formula 1wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X-Z and 2are as described herein.A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing such aP2 inhibitor or a combination of such aP2 inhibitor and another antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin. Excerpt(s): The present invention relates to heterocyclic containing biphenyls which are inhibitors of aP2 and to a method for treating diabetes, especially Type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, Syndrome X, diabetic complications, atherosclerosis and related diseases, and other chronic inflammatory and autoimmune/inflammatory diseases, employing such heterocyclic containing biphenyls

270 Insulin

alone or in combination with one or more types of antidiabetic agents. Fatty acid binding proteins (FABPs) are small cytoplasmic proteins which bind to fatty acids such as oleic acids which are important metabolic fuels and cellular regulators. Dysregulation of fatty acid metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes). aP2 (adipocyte fatty binding protein), an abundant 14.6 KDa cytosolic protein in adipocytes, and one of a family of homologous intracellular fatty acid binding proteins (FABPs), is involved in the regulation of fatty acid trafficking in adipocytes and mediates fatty acid fluxes in adipose tissue. G. S. Hotamisligil et al, "Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein", Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report that aP2-deficient mice placed on a high fat diet for several weeks developed dietary obesity, but, unlike control-mice on a similar diet, did not develop insulin resistance or diabetes. Hotamisligil et al conclude that "aP2 is central to the pathway that links obesity to insulin resistance" (Abstract, page 1377). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions Inventor(s): Bastos, Margarita M.; (Plainsboro, NJ), Bernatowicz, Michael; (Princeton, NJ), Ewing, William R.; (Yardley, PA), Lee, Ving; (Hamilton, NJ), Mapelli, Claudio; (Plainsboro, NJ), Natarajan, Sesha Iyer; (Hillsborough, NJ) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030195157 Date filed: October 18, 2002 Abstract: The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. Excerpt(s): This application claims the benefit of provisional application U.S. Serial No. 60/342,015, filed Oct. 18, 2001, the disclosure of which is hereby incorporated by reference herein in its entirety. The present invention provides novel human glucagonlike peptide-1 (GLP-1) peptide mimics, which duplicate the biological activity of the native peptide, exhibit increased stability to proteolytic cleavage as compared to GLP-1 native sequences, and thus are useful for the amelioration of the diabetic condition. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 30 amino acid residue peptide originating from preproglucagon, which is synthesized for example, in the Lcells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to yield GLP-1(7-36)amide and GLP-2 occurs mainly in the L-cells. GLP-1 is normally secreted in response to food intake, in particular carbohydrates and lipids stimulate GLP-1 secretion. GLP-1 has been identified as a very potent and efficacious stimulator for insulin release. GLP-1 lowers glucagon concentration, slows gastric emptying,

Patents 271

stimulates insulin biosynthesis and enhances insulin sensitivity (Nauck, 1997, Horm. Metab.Res. 47:1253-1258). GLP-1 also enhances the ability of the B-cells to sense and respond to glucose in subjects with impaired glucose tolerance (Byrne, Eur. J. Clin. Invest., 28:72-78, 1998). The insulinotropic effect of GLP-1 in humans increases the rate of glucose metabolism partly due to increased insulin levels and partly due to enhanced insulin sensitivity (D'Alessio, Eur. J. Clin. Invest., 28:72-78, 1994). The above stated pharmacological properties of GLP-1 make it a highly desirable therapeutic agent for the treatment of type-II diabetes. Additionally, recent studies have shown that infusions of slightly supraphysiological amounts of GLP-1 significantly enhance satiety and reduce food intake in normal subjects (Flint, A., Raben, A., Astrup, A. and Holst, J. J., J.Clin.Invest, 101:515-520, 1998; Gutswiller, J. P., Goke, B., Drewe, J., Hildebrand, P., Ketterer, S., Handschin, D., Winterhaider, R., Conen, D and Beglinger, C. Gut 44:81-86, 1999;). The effect on food intake and satiety has also been reported to be preserved in obese subjects (Naslund, E., Barkeling, B., King, N., Gutniak, M., Blundell, J. E., Holst ,J. J., Rossner, S., and Hellstrom, P. M., Int. J. Obes. Relat. Metab. Disord., 23:304-311, 1999). In the above-cited studies a pronounced effect of GLP-1 on gastric emptying was also suspected to occur. Gastric emptying results in post-prandial glucose excursions. It has also been shown that in addition to stimulation of insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating B-cell neogenesis and may thereby be an effective treatment and/or preventive agent for diabetes (Stoffers, D. A., Kieffer, T. J. Hussain, M. A.,Drucker, D. J., Bonner-Weir, S., Habener, J. F. and Egan, J. M. Diabetes, 40:741-748, 2000). GLP-1 has also been shown to inhibit gastric acid secretion (Wettergren, A., Schjoldager, B., Mortensen, P. E., Myhre, J., Christiansen, J., Holst, J. J., Dig. Dis. Sci., 38:665-673, 1993), which may provide protection against gastric ulcers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Induction of insulin-producing cells Inventor(s): Ishizuka, Nobuko; (Chiba-shi, JP), Okuno, Masaaki; (Chiba-shi, JP), Seino, Susumu; (Chiba-shi, JP) Correspondence: Greenblum & Bernstein, P.L.C.; 1950 Roland Clarke Place; Reston; VA; 20191; US Patent Application Number: 20030219894 Date filed: April 15, 2003 Abstract: What is described is a method for preparation of insulin-producing cells from non-insulin-producing cells. Mammalian fetal hepatocytes or hepatic progenitor cells are used ad the non-insulin-producing cells, and the method comprises culturing the mammalian fetal hepatocytes or the hepatic progenitor cells with 1-50 mmol/L of nicotinamide and concurrently bringing about expression of the PDX-1 gene or the NeuroD gene in the mammalian fetal hepatocytes. Excerpt(s): The present invention relates to preparation of insulin-producing cells from non-insulin-producing cells, and in particular to preparation of insulin-producing cells from hepatocytes. Since its discovery, insulin has been generally used for the treatment of diabetic patients with absolute insulin deficiency. However, while normal pancreatic.beta.-cells continuously adjust insulin secretion in response to varying blood glucose levels, exogenous insulin administration cannot confine the levels of blood glucose within a physiological range, within which the development of various diabetic complications could be prevented. Although transplantation of pancreas or pancreatic

272 Insulin

islets can achieve normoglycemia in absolute insulin insufficiency [Robertson R P et al., Diabetes Care 23:112-116 (2000)], the shortage of transplantable pancreas or pancreatic islets, in particular, makes this approach impractical. For this reason, transplantation of pancreatic.beta.-cells or islets generated from stem cells has become more promising therapeutic approach to achieving normoglycemia [Soria B et al., Diabetes 49:157-162 (2000), Lumelsky N et al., Science 292:1389-1394 (2001), Assady S et al., Diabetes 50:16911697 (2001)]. The first step of a cell therapy for diabetes mellitus is to generate insulinsecreting cells that are implantable into the patients. While the establishment of embryonic stem cell (ES cell) lines has provided a useful system to examine the mechanisms of differentiation of stem cells into a variety of types of cells, there are daunting obstacles to the clinical use of ES cells. Allotransplantation of human ES cell derivatives into patients generally would elicit an immune response similar to that is elicited to transplanted pancreatic islets or transplanted pancreas [Odorico J S et al., Stem Cells 19:193-204 (2001)]. In addition, transplantation of ES cell derivatives into human recipients might result in the formation of ES cell-derived tumors [Odorico J S et al., Stem Cells 19:193-204 (2001)]. Ethical issues also would arise in acquiring human ES cell derivatives [McLaren A et al., Nature 414:129-131 (2001)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Insulin and IGF-1 receptor agonists and antagonists Inventor(s): Blume, Arthur J.; (Annandale, NJ), Brandt, Jakob; (Broenshoej, DK), Brissette, Renee; (Edison, NJ), Goldstein, Neil I.; (Maplewood, NJ), Hansen, Per Hertz; (Lyngby, DK), Ostergaard, Soren; (Broenshoej, DK), Pillutla, Renuka; (Bridgewater, NJ), Schaffer, Lauge; (Copenhagen, DK), Spetzler, Jane; (Copenhagen, DK) Correspondence: Morgan & Finnegan, L.L.P.; 345 Park Avenue; New York; NY; 101540053; US Patent Application Number: 20030195147 Date filed: September 24, 2001 Abstract: Peptide sequences capable of binding to insulin and/or insulin-like growth factor receptors with either agonist or antagonist activity and identified from various peptide libraries are disclosed. This invention also identifies at least two different binding sites, which are present on insulin and insulin-like growth factor receptors, and which selectively bind the peptides of this invention. As agonists, certain of the peptides of this invention may be useful for development as therapeutics to supplement or replace endogenous peptide hormones. The antagonists may also be developed as therapeutics. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/538,038 filed Mar. 29, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/146,127, filed Sep. 2, 1998, both of which are incorporated by reference in their entirety. This invention relates to the field of hormone receptor activation or inhibition. More specifically, this invention relates to the identification of molecular structures, especially peptides, which are capable of acting at either the insulin or insulin-like growth factor receptors as agonists or antagonists. Also related to this invention is the field of molecular modeling whereby useful molecular models are derived from known structures. Insulin is a potent metabolic and growth promoting hormone that acts on cells to stimulate glucose, protein, and lipid metabolism, as well as RNA and DNA synthesis. A well-known effect of insulin is the regulation of glucose levels in the body. This effect occurs predominantly in liver, fat, and muscle tissue. In the liver, insulin

Patents 273

stimulates glucose incorporation into glycogen and inhibits the production of glucose. In muscle and fat tissue, insulin stimulates glucose uptake, storage, and metabolism. Defects in glucose utilization are very common in the population, giving rise to diabetes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Insulin purification using simulated moving bed technology Inventor(s): Mun, Sungyong; (West Lafayette, IN), Wang, Nien-Hwa Linda; (West Lafayette, IN), Xie, Yi; (West Lafayette, IN) Correspondence: King & Spalding; 191 Peachtree Street, N.E.; Atlanta; GA; 30303-1763; US Patent Application Number: 20030216543 Date filed: April 7, 2003 Abstract: Simulated moving beds for the chromatographic purification of insulin are provided. The insulin can be resolved from one or more components, using one or more simulated moving bed rings. Methods for designing simulated moving beds for the purification of insulin, and optimizing the operating parameters of the simulated moving beds, are also provided based upon the standing wave design. Excerpt(s): This application claims priority to U.S. Provisional Patent Application No. 60/204,701, filed May 16, 2000. This invention relates to the purification of insulin from binary and multicomponent mixtures using simulated moving bed technology. The invention is applicable generally to systems exhibiting linear isotherms, and is especially applicable to such systems when separations are inhibited by mass transfer resistances. Liquid chromatography is widely used in industry for separating and purifying components in liquid and gaseous mixtures. However, most applications of liquid chromatography are batch chromatographic processes, which give low yields, consume high quantities of eluent, utilize adsorbent inefficiently, and are labor intensive. Moreover, the discontinuous nature of batch chromatography, and the dilution of collected components, limits its attractiveness for pilot-plant and process-scale separations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Insulin-mediated glucose uptake monitor Inventor(s): Houben, Richard; (Lanaken, BE) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20030199925 Date filed: April 22, 2002 Abstract: An implanted medical device may detect the onset of impaired glucose tolerance or Type II diabetes. The implanted medical device may have additional functionality. For example, the implanted medical device may be a pacemaker or a pressure monitor, but may also monitor insulin-mediated glucose uptake by processing electrical signals from the heart. An implanted medical device that monitors insulinmediated glucose uptake may be implanted in a patient who has not been diagnosed

274 Insulin

with impaired glucose tolerance or Type II diabetes, and may give the patient early warning if these conditions develop. Excerpt(s): The invention relates to patient monitoring systems, and more particularly, to patient monitoring systems that receive an electrical cardiac signal indicative of cardiac activity. Diabetes mellitus is the most common of endocrine disorders, and is characterized by inadequate insulin action. Diabetes mellitus has two principal variants, known as Type I diabetes and Type II diabetes. The latter is also referred to as DM/II (diabetes mellitus type II), adult-onset diabetes, maturity-onset diabetes, or NIDDM (non-insulin dependent diabetes mellitus). Type II diabetes generally develops in adulthood, and the risk of development of Type II diabetes increases with age. Factors such as obesity also contribute to the risk. A patient suffering from Type II diabetes secretes insulin, but the insulin's target cells are less sensitive to insulin. Symptoms of Type II diabetes are typically slow to appear, and a patient having Type II diabetes may not be aware of his condition. A blood test may show whether the patient has impaired glucose tolerance (IGT), which is often a precursor to Type II diabetes, or compensated Type II diabetes. Unless addressed with treatment such as diet and exercise, these conditions may develop into uncompensated Type II diabetes, a very serious condition. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for real-time control of physiological parameters Inventor(s): Buckingham, Bruce A.; (Palo Alto, CA), Knobbe, Edward J.; (Fallbrook, CA), Lim, Wah L.; (Newport Beach, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030195404 Date filed: April 16, 2003 Abstract: A real-time controller operating as an artificial pancreas uses a Kalman control algorithm to control glucose level of a patient in real time. The real-time controller receives an estimate of the patient glucose level and a reference glucose level. The estimate of the patient glucose level can be provided by an optimal estimator implemented using a linearized Kalman filter. The estimated glucose level and the reference glucose level are processed by the Kalman control algorithm to determine a control command in real time. The Kalman control algorithm has a dynamic process forced by the control command a cost function determining a relative level of control. The control command is provided to a dispenser which secretes insulin or glucagon in response to the control command to correct a relatively high glucose level or a relatively low glucose level. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/960,855, filed on Sep. 21, 2001, which claims the benefit of U.S. Provisional Application No. 60/234,632, filed on Sep. 22, 2000, and entitled Real Time Estimation & Control Of Biological Process. A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or of the patent disclosure as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all copyright rights whatsoever. This present invention relates generally to a method and apparatus for controlling physiological parameters and more particularly to an optimal controller for controlling glucose levels in a patient.

Patents 275

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for making insulin precursors and insulin precursor analogs Inventor(s): Kaarsholm, Niels C.; (Vanlose, DK), Kjeldsen, Thomas Borglum; (Virum, DK), Ludvigsen, Svend; (Lynge, DK) Correspondence: Reza Green, ESQ.; Novo Nordisk Pharmaceuticals, INC.; 100 College Road West; Princeton; NJ; 08540; US Patent Application Number: 20030191277 Date filed: December 11, 2002 Abstract: Novel insulin precursors and insulin precursor analogs having a mini Cpeptide comprising at least one aromatic amino acid residue have an increased folding stability. The novel insulin precursors and insulin precursor analogs can be expressed in yeast in high yields and are preferably not more 15 amino acid residues in length. Also provided are polynucleotide sequences encoding the claimed precursors or precursor analogs, and vectors and cell lines containing such polynucleotide sequences. Excerpt(s): Yeast organisms produce a number of proteins that have a function outside the cell. Such proteins are referred to as secreted proteins. These secreted proteins are expressed initially inside the cell in a precursor or a pre-form containing a pre-peptide sequence ensuring effective direction (translocation) of the expressed product across the membrane of the endoplasmic reticulum (ER). The pre-peptide, normally named a signal peptide, is generally cleaved off from the desired product during translocation. Once entered in the secretory pathway, the protein is transported to the Golgi apparatus. From the Golgi, the protein can follow different routes that lead to compartments such as the cell vacuole or the cell membrane, or it can be routed out of the cell to be secreted to the external medium (Pfeffer et al. (1987) Ann. Rev. Biochem. 56:829-852). Insulin is a polypeptide hormone secreted by O-cells of the pancreas and consists of two polypeptide chains, A and B, which are linked by two inter-chain disulphide bridges. Furthermore, the A-chain features one intra-chain disulphide bridge. The hormone is synthesized as a single-chain precursor proinsulin (preproinsulin) consisting of a prepeptide of 24 amino acid followed by proinsulin containing 86 amino acids in the configuration: prepeptide-B-Arg Arg-C-Lys Arg-A, in which C is a connecting peptide of 31 amino acids. Arg-Arg and Lys-Arg are cleavage sites for cleavage of the connecting peptide from the A and B chains. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Method of treatment of obesity and paralyzed muscle and ergogenic aids Inventor(s): Winder, William W; (Provo, UT) Correspondence: Madson & Metcalf; Gateway Tower West; Suite 900; 15 West South Temple; Salt Lake City; UT; 84101 Patent Application Number: 20030212034 Date filed: December 2, 2002 Abstract: The invention relates to a method of treating obesity in a mammal. The method includes the step of administering a therapeutically effective amount of an AMP-activated protein kinase activator to the mammal. The mammal may be for

276 Insulin

example, a human, a rat, a mouse, and the like. The AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal. The activation of the AMP-activated protein kinase activator can produce the benefits of exercise training including the loss of body fat. The invention also relates to a method of treating insulin resistance in a mammal suffering from obesity, type 2 diabetes, or muscle paralysis. To reduce the insulin resistance a therapeutically effective amount of an AMP-activated protein kinase activator is given to the mammal. Excerpt(s): This application is related to and claims the benefit of U.S. Provisional Application Serial No. 60/210,708 of William W. Winder Jun. 9, 2000 and entitled "Use of AMP Kinase Activators for Treatment of Obesity and Paralyzed Muscle and as Ergogenic Aids," which is incorporated herein by this reference. The present invention relates to the methods of treatment of obesity and paralyzed muscle. More specifically, the invention relates methods of treatment of obesity and paralyzed muscle through artificial activation of metabolic pathways. Obesity is one of the largest health problems in the United States and is a growing concern for many health care officials. By one account more than 33 percent of adults and 20 percent of children in the United States are considered obese. Obesity is defined as having excessive amounts of body fat. Body fat (adipose tissue) is necessary for certain bodily functions. However, when body fat accumulates to excessive amounts the person is considered obese. Obesity can lead to a number of different illness including: heart disease, high blood pressure, increased cholesterol, diabetes, certain types of cancer, orthopedic problems, musculo-skeletal diseases, decreased flexibility, and difficulty breathing. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and compositions for the treatment and diagnosis of body weight disorders Inventor(s): Gimeno, Ruth; (Wellesley, MA), Spiegelman, Bruce M.; (Waban, MA) Correspondence: Lahive & Cockfield; 28 State Street; Boston; MA; 02109; US Patent Application Number: 20030212016 Date filed: May 13, 2002 Abstract: The present invention relates to methods and compositions for the treatment and diagnosis of body weight disorders, including, but not limited to, obesity, overweight, anorexia, cachexia, insulin resistance, and diabetes. The invention further provides methods for identifying a compound capable of treating a body weight disorder or modulating thermogenesis. The invention also provides a method for modulating thermogenesis, e.g., modulating thermogenesis in a subject. In addition, the invention provides a method for treating a subject having a body weight disorder characterized by aberrant DHDR-2 polypeptide activity or aberrant DHDR-2 nucleic acid expression. In another aspect, the invention provides methods for modulating thermogenesis in a subject. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/289,917, filed May 9, 2001, the entire contents of which are incorporated herein by this reference. Obesity represents the most prevalent of body weight disorders, with estimates ranging from 30% to 50% within the middle-aged population in the western world. Other body weight disorders, such as anorexia nervosa and bulimia nervosa which together affect approximately 0.2% of the female population of the western

Patents 277

world, also pose serious health threats. Further body weight disorders such as anorexia and cachexia (wasting) are also prominent features of other diseases such as cancer, cystic fibrosis, and AIDS. Obesity, defined as a body mass index (BMI) of 30 kg/.sup.2m or more, also contributes to other diseases. For example, this disorder is responsible for increased incidences of diseases such as coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia and some cancers (see, e.g., Nishina, P. M. et al. (1994) Metab. 43:554-558; Grundy, S. M. and Barnett, J. P. (1990), Dis. Mon. 36:641-731). Obesity is a complex multifactorial chronic disease that develops from an interaction of genotype and the environment. The development of obesity involves social, behavioral, cultural, physiological, metabolic and genetic factors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods fo treating conditions associated with insulin resistance with aicar, (5amino-4-imidazole carboxamide riboside) and related compounds Inventor(s): Ido, Yasuo; (Brookline, MA), Kraegen, Edward W; (Sydney, AU), Ruderman, Neil; (Newton, MA) Correspondence: Weingarten, Schurgin, Gagnebin & Lebovici Llp; Ten Post Office Square; Boston; MA; 02109; US Patent Application Number: 20030212014 Date filed: March 12, 2003 Abstract: The long-term usage of AICR (5-aminio, 4-imidazole carboxamide riboside) to produce sustained metabolic and biological changes in mammals that overcome insulin resistance, i.e., increase insulin sensitivity, and result in benefits in diseases and conditions such as diabetes, hypertension, atherosclerosis, polycystic ovary syndrome and gallstones is described long-term usage of AICAR, particularly intermittent administration, e.g., three days per week, appears to have some of the positive effects of exercise, having an impact on the amount Of food consumed by a subject and resulting in reduced fat build-up and increase in muscle mass. Therefore, AICAR administration has a positive impact in reducing obesity. AICAR can also Prove useful in preventing or treating vascular diseases associated with hyperglycemia, high plasma levels of free fatty acids (FFA) and triglyceride, and insulin resistance by virtue of the fact that this agent activates fatty acid oxidation. Animal tests have Shown that chronic intermittent treatment with AICAR has not resulted in any noticeable toxic effects. AICAR and related compounds are activators of AMP-activated protein kinase (AMPK) and, furthermore, are effective at decreasing malonyl CoA levels in the animal. Excerpt(s): This application claims the priority of the following applications: U.S. Provisional Application No. 60/222,131, filed Jul. 31, 2000 entitled, USE OF AICAR (5AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS TO TREAT INSULIN RESISTANCE; International Application No. PCT/US00/40607, filed Aug. 9, 2000 entitled, METHOD OF MAINTAINING VASCULAR INTEGRITY USING AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS; and International Application No. PCT/US01/18467 filed Jun. 6, 2001 entitled, USE OF AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS FOR THE PREVENTION AND TREATMENT OF OBESITY, the whole of which are hereby incorporated by reference herein. AMP-activated protein kinase (AMPK) is a cytoplasmic enzyme that has been shown to exist in both the liver and skeletal muscle. As its name indicates, AMPK is activated by increasing levels of AMP and, secondarily, by an increase in the ratio of

278 Insulin

AMP to ATP in the cell. AMP levels rise in the cell as ATP is hydrolyzed to ADP and Pi. Two molecules of ADP, through the action of myokinase, also known as adenylate kinase, produce one molecule of ATP and one molecule of AMP. In addition to its activation by AMP, AMPK is activated through phosphorylation by an upstream kinase called AMPK kinase (AMPKK). AMP also allosterically activates AMPKK. Phosphorylation of AMPK by AMPKK makes it a poor substrate for phosphatases. All these factors combined together make AMPK very sensitive to minimal fluctuations in cellular AMP levels. AMPK has several known substrates, specifically enzymes that it can phosphorylate and modulate. In the liver, AMPK has been shown to phosphorylate hydroxymethyl glutaryl CoA (HMGCOA) reductase and acetyl CoA carboxylase (ACC), inhibiting the actions of both enzymes. Reducing HMGCOA reductase activity inhibits cholesterol synthesis, and reducing ACC activity decreases the generation of malonyl CoA, an intermediate in fatty acid synthesis. In skeletal muscle, AMPK also is an inhibitor of carnitine palmitoyl transferase I, which regulates the uptake of fatty acids into mitochondria where they are oxidized. In addition, AMPK has been shown to increase glucose transport into the muscle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Modified biological peptides with increased potency Inventor(s): Abribat, Thierry; (Montreal, CA), Gravel, Denis; (St-Lambert, CA), Habi, Abdelkrim; (Anjou, CA) Correspondence: David S Resnick; Nixon Peabody; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20030204063 Date filed: March 3, 2003 Abstract: The present invention is concerned with modified biological peptides providing increased potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent, either at the N-terminal of the peptide, the Cterminal of the peptide, on a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. Those peptides exhibit clinical usefulness for example in treating states of insulin resistance associated with pathologies such as type II diabetes. Excerpt(s): The present invention is concerned with modified peptides providing increased biological potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent either at the N-terminal of the peptide, the Cterminal of the peptide, or a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. Most peptides are rapidly degraded in a serum medium and as a result, their metabolites may sometimes end up with little or no residual biological activity. To increase the activity of a peptide, various techniques have been proposed. One of them is to anchor a hydrophobic chain at the N- or C-terminal of the peptidic sequence or at other residues along the peptidic chain. This technique nevertheless has limitations. For example, if the peptide comprises a long peptidic chain, the fact that a small hydrophobic group is anchored to the N- or C-terminal does not necessarily result in an increased activity of the peptide so-modified. For example, it is known that substituting OH for a more hydrophobic group like --NEt.sub.2 at the C-terminal of a peptide sequence can result in a significantly increased specific activity. However, these results are contradicted by several publications, such as Muranichi et al. in Pharm. Res.,

Patents 279

1991, 8, 649-652, which stresses the inefficiency of a lauroyl group as a hydrophobic group at the N-terminal to increase activity. Accordingly, there does not seem to be any general rule or conclusion concerning biological potency, duration of activity and/or half life, that can be derived as a result of the addition of substituents on a peptide chain, whether at the N- or C-terminal, or on certain residues along the peptidic chain. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Modified proinsulin variants and composition containing same Inventor(s): Dubaquie, Yves; (San Francisco, CA), Lowman, Henry; (El Granada, CA) Correspondence: Heller Ehrman White & Mcauliffe Llp; 275 Middlefield Road; Menlo Park; CA; 94025-3506; US Patent Application Number: 20030191065 Date filed: May 22, 2003 Abstract: IGF-I and insulin variants are provided that selectively bind to IGFBP-1 or IGFBP-3. These agonist variants are useful, for example, to improve the half-lives of IGFI and insulin, respectively. Excerpt(s): This invention relates to molecules useful as agonists of the insulin-like growth factors (IGFs), as well as IGF-like insulin molecules. More particularly, these molecules inhibit the interaction of an IGF or insulin with one or more of the IGF binding proteins. Such molecules can be used, for example, in any methods where the IGFs or insulins are used, for example, in treating hyperglycemic, obesity-related, neurological, cardiac, renal, immunologic, and anabolic disorders. The insulin-like growth factors I and II (IGF-I and IGF-II, respectively) mediate multiple effects in vivo, including cell proliferation, cell differentiation, inhibition of cell death, and insulin-like activity (reviewed in Clark and Robinson, Cytokine Growth Factor Rev., 7: 65-80 (1996); Jones and Clemmons, Endocr. Rev., 16: 3-34 (1995)). Most of these mitogenic and metabolic responses are initiated by activation of the IGF-I receptor, an.alpha.sub.2.beta.sub.2-heterotetr- amer closely related to the insulin receptor (McInnes and Sykes, Biopoly., 43: 339-366 (1998); Ullrich et al., EMBO J., 5: 2503-2512 (1986)). Both proteins are members of the tyrosine kinase receptor superfamily and share common intracellular signaling cascades (Jones and Clemmons, supra). IGFinsulin hybrid receptors have been isolated, but their function is unknown. The IGF-I and insulin receptors bind their specific ligands with nanomolar affinity. IGF-I and insulin can cross-react with their respective non-cognate receptors, albeit at a 100-1000fold lower affinity (Jones and Clemmons, supra). The crystal structure describing part of the extracellular portion ofthe IGF-I receptor has recently been reported (Garrett et al., Nature, 394: 395-399 (1998)). Unlike insulin, the activity and half-life of IGF-I are modulated by six IGF-I binding proteins (IGFBP's 1-6), and perhaps additionally by a more distantly-related class of proteins (Jones and Clemmons, supra; Baxter et al., Endocrinology, 139: 4036 (1998)). IGFBP's can either inhibit or potentiate IGF activity, depending on whether they are soluble or cell-membrane associated (Bach and Rechler, Diabetes Reviews, 3: 38-61 (1995)). The IGFBPs bind IGF-I and IGF-II with varying affinities and specificities (Jones and Clemmons, supra; Bach and Rechler, supra). For example, IGFBP-3 binds IGF-I and IGF-II with a similar affinity, whereas IGFBP-2 and IGFBP-6 bind IGF-II with a much higher affinity than they bind IGF-I (Bach and Rechler, supra; Oh et al, Endocrinology, 132, 1337-1344 (1993)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

280 Insulin

•

Multiparticulate compositions for once-a-day administration Inventor(s): Bhagwatwar, Harshal Prabhakar; (Aurangabad, IN), Chaudhari, Sunil Sudhakar; (Aurangabad, IN), De Souza, Noel John; (Mumbai, IN), Malhotra, Manjusha; (New Delhi, IN), Saoji, Dilip Gopalkrishna; (Aurangabad, IN), Shukla, Milind C.; (Aurangabad, IN) Correspondence: Kenyon & Kenyon; One Broadway; New York; NY; 10004; US Patent Application Number: 20030219482 Date filed: March 20, 2003 Abstract: A pharmaceutical composition suitable for a once-a-day dosing regimen includes a combination of a biguanide and a sulfonylurea in the form of a multiparticulate, polyphasic system for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and for improving glycemic control. Excerpt(s): The present invention relates to a pharmaceutical composition suitable for a once-a-day dosing regimen comprising a combination of a biguanide and a sulfonylurea in the form of a multiparticulate, polyphasic system for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and for improving glycemic control. Diabetes mellitus of type II is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications: the microvascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet and exercise is the mainstay of treatment of type II diabetes. However, these are followed by administration of oral hypoglycemic agents. Current drugs used for managing type II diabetes and its precursor syndromes such as insulin resistance, include classes of compounds such as for example, biguanides and sulfonylureas, among others. Biguanides, represented principally by metformin, phenformin and buformin, help in the control of blood glucose by decreasing hepatic glucose production and reducing intestinal absorption of glucose. Sulfonylureas, represented principally by glipizide, glimiperide, glyburide, glibomuride, glisoxepide, gliclazide acetohexamide, chlorpropamide, tolazamide, and tolbutamide, among others, help in controlling or managing NIDDM by stimulating the release of insulin from the pancreas. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Novel mechanism for identifying drugs for the treatment of type II diabetes Inventor(s): Berggren, Per-Olof; (Solna, SE), Leibiger, Barbara; (Solna, SE), Leibiger, Ingo; (Solna, SE) Correspondence: Timothy A. French; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030215804 Date filed: March 28, 2002 Abstract: Insulin resistance is a central feature of type II diabetes and other diseases, and may affect every tissue of the body, including the pancreatic beta cell. Insulin signaling is mediated by a complex network of diverging and converging pathways, with

Patents 281

alternative proteins and isoforms at almost every step in the process. We have previously shown that insulin activates the transcription of its own gene by signaling through Insulin Receptor A type (Ex11-), PI3 kinase and p70 s6 kinase. When studying the mechanisms underlying the glucose-stimulated activation of the glucokinase gene in pancreatic beta cells, we now demonstrate that also here secreted insulin is a key-factor. In contrast to the insulin gene, transcription of the glucokinase gene is promoted by signaling via Insulin Receptor B type (Ex11+) and protein kinase B (c-Akt). These data provide the first evidence for selectivity in insulin action via the two isoforms of the Insulin Receptor, A type (Ex11-) and B type (Ex11+), and reinforce the concept of the beta cell being an important target of insulin action. Excerpt(s): Understanding selectivity in signal transduction is one of the most challenging tasks in current cell biology. Over the years, insulin signaling has served as one of the model examples in hormone-induced signal transduction. Complete loss of either insulin or Insulin Receptors (IRs) is lethal. Malfunction of insulin signaling, referred to as insulin resistance, is one of the major causes of type II diabetes (type 2 diabetes mellitus, non-insulin-dependent diabetes mellitus, NIDDM), the most common metabolic disorder in man. Insulin has been shown to exhibit pielotropic effects, involving mitogenic and/or metabolic events. Moreover, the effect of insulin is tissue-as well as development-dependent. The fact that insulin may transduce its signal through a variety of pathways has been discussed in extensive detail (White and Kahn, 1994). The three major pathways described to date, which employ Insulin Receptors (IRs) as the primary target, include signaling via mitogen activated protein (MAP) kinases, phospholnositol-3 kinase (PI3K) and phospholipase C. The Insulin Receptor, the first step in these cascades, as a result of alternative mRNA spicing of the 11.sup.th exon of the (prepro)Insulin Receptor transcript, exists in two isoforms. The A type, or Ex11- (Ullrich et al., 1985), lacks, whereas the B type, or Ex11+ (Ebina et al., 1985), contains the respective sequence coding for 12 amino acids in the C-terminus of the.alpha.-chain of the receptor. To date, no insulin-induced effect has been reported that discriminates signaling via A and B type receptors. In fact, the functional significance of these Insulin Receptor (IR) isoforms remains unclear (for a review see Flier et al 1996). Recent studies have shown that also the insulin-producing pancreatic beta cell is a target for insulin action, with insulin effects on transcription, translation, ion flux and exocytosis of insulin (Leibiger et al., 1998a; Kulkarni et al., 1999; Leibiger et al., 2000). In an animal model with a beta cell-specific knockout for Insulin Receptors, a decrease in glucose stimulated insulin release has been shown and a decrease in the insulin content of the cell (Kulkarni et al., 1999). In addition, disruption of insulin signaling in the beta cell at the level of Insulin Receptor substrate-1 or Insulin Receptor substrate-2 leads to altered growth and function of the beta cell. Consequently, insulin resistance, one of the major causes of type II diabetes may not only affect the function of the `classical` insulin target tissues; muscle, fat and liver, but also apply to the pancreatic beta cell and therefore may affect beta cell function. In the present application, for the first time, selective insulin signaling via the two isoforms of the Insulin Receptor (IR), i.e. IR-A and IR-B type, is shown in a pancreatic beta cell. It is demonstrated that insulin secreted by pancreatic beta cells, upon glucose stimulation, up-regulates insulin gene transcription in an autocrine feedback loop. This autoregulation is mediated by insulin signaling via the A type Insulin Receptor, involving phosphoinositol-3 kinase class Ia, p70s6 kinase and Ca.sup.2+/calmodulin dependent kinases. Stimulation with either glucose or insulin also leads to an upregulated expression of the beta-cell transcription unit of the glucokinase gene (.beta.GK). However, in contrast to insulin-stimulated insulin gene transcription, the effect of insulin on beta cell glucokinase gene transcription occurs via the type B Insulin

282 Insulin

Receptor and protein kinase B (PKB/c-Akt) involving class II-like phospholnositol-3 kinase. The results described in the present application provide evidence that signaling via either A or B type Insulin Receptors represents a mechanism for selective insulin action. The surprising findings described herein provide the basic for a first IR-isoformspecific readout system. Thus, the pancreatic beta cell can henceforth serve as a screening tool for drugs and insulin mimetics, wherein IR-A-specific signaling leads to insulin promoter activation and IR-B-specific signaling up-regulates the.beta.GK promoter. In a screening system, measurement of either insulin- and.beta.GK-mRNA levels or insulin- and.beta.GK-promoter-driven reporter gene expression can be employed as the actual readout tool. The IR-isoform-specific readout system comprised in the invention can further be used as a screening tool that will allow the development of compounds such as drugs and/or insulin mimetics, that selectively activate either IRA or IR-B-specific signaling cascades, e.g. in the beta cell and in peripheral tissues. The pronounced expression of IR-B in the classical insulin target tissues implies the importance of the IR-B signaling cascade in these tissues. Consequently, the development of compounds that selectively stimulate the IR-B signaling cascade will improve the function of the beta cell (glucose responsiveness and therefore insulin secretion), as well as the function of the peripheral insulin target tissues (glucose uptake and utilization, protein synthesis, lipid synthesis) and thus potentially provide a treatment that covers the two major causes of non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes), i.e. peripheral insulin resistance and beta cell dysfunction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oil/fat composition Inventor(s): Hase, Tadashi; (Tochigi, JP), Katsuragi, Yoshihisa; (Tokyo, JP), Koike, Shin; (Tokyo, JP), Murase, Takatoshi; (Tochigi, JP), Takei, Akira; (Tokyo, JP), Yasumasu, Takeshi; (Tokyo, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030198727 Date filed: February 10, 2003 Abstract: Provided is an oil/fat composition comprising 10.1 to 94.9 wt. % of a triglyceride, 0.1 to 30 wt. % of a monoglyceride and 5 to 59.9 wt. % of a diglyceride which has, as a fatty acid constituent thereof, 15 to 90 wt. % of an.omega.3-unsaturated fatty acid having less than 20 carbon atoms. The oil/fat composition of the present invention has excellent heat stability, has body-fat-accumulation resisting action, visceral-fat-accumulation resisting action, blood-sugar-level lowering action, insulin resistance improving action and leptin lowering action and is useful for, as well as pharmaceuticals, preventive or remedial food for diabetes or obesity, and feed. Excerpt(s): The present invention relates to an oil/fat composition having a specific glyceride composition and a specific fatty acid composition, having excellent heat stability, having a body-fat-accumulation resisting action and a visceral-fataccumulation resisting action, and being extremely useful for health. Lipids (oils or fats), important nutrients in addition to proteins and carbohydrates, are particularly useful as an energy source. It however has a high calorie (9 kcal/g) and intake of it promotes obesity and can be causative of problems such as life-style related diseases. A meal rich in lipids are typically delicious and people of the present day are accustomed to such a meal. In advanced countries under satiation, an increase in lipidic intake has come to be

Patents 283

a serious nation-wide problem together with a rise in medical expenses. In recent days, people are highly interested particularly in health promotion and maintenance and preventive treatment of diseases and a number of investigations have been made on the relationship between lipids and obesity or life-style related diseases. Primary investigations to date have been related to fatty acids constituting a triglyceride, a principal component of a lipid. Nutritionally essential fatty acids are, for example, linoleic acid, arachidonic acid and linolenic acid. These fatty acids are known to be utilized in the body as a constituent of a biomembrane or a raw material of eicosanoids (prostaglandin, thromboxanes, leukotrienes, etc.). In addition, it is reported that there is a high possibility of saturated fatty acids in a diet having a blood-serum cholesterol heightening action, leading to atherosclerosis or heart diseases (Lancet, 2, 959(1950)); and a high linoleic acid oil contained much in a diet increases tumor incidence and size of experimental animals (J. National Cancer Institute, 66, 517(1971)). It is described that an oleic-acid-rich and saturated-fatty-acid-poor diet lowers LDL-cholesterol level, while maintaining an HDL-cholesterol level, thereby reducing the risk of heart diseases (J. Lipid Res., 26, 194(1985), New England J. Medicine, 314, 745(1988)). In addition, physiological activities of various.omega.3-unsaturated fatty acids including antithrombus effects of eicosapentaenoic acid contained in a fish oil have drawn attention (Ann. Rev. Nutr., 8, 517(1988)). On the other hand, owing to many double bonds, eicosapentaenoic acid or docosahexaenoic acid involves a problem in stability against oxidation; and eicosapentaenoic acid has an anticoagulant action. Based on the study of intake balance of these fatty acids, a number of research reports have been presented, for example, on a recommendable ratio of saturated fatty acid:monounsaturated fatty acid:polyunsaturated fatty acid or a ratio of 6-unsaturated fatty acid:.omega.3-unsaturated fatty acid. Research is still in progress (Nutrition and Diseases of Oils and Fats", published by Saiwai Shobo, The 6.sup.th edition of Recommended Dietary Allowances for Japanese", Ministry of Health and Welfare). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oral insulin therapy Inventor(s): Abbas, Richat; (Mohegan Lake, NY), Arbit, Ehud; (Tarrytown, NJ), Dinh, Steven; (Tarrytown, NY), Goldberg, Michael M.; (Tarrytown, NJ), Woods, T. Cooper; (New York, NY) Correspondence: Davidson, Davidson & Kappel, Llc; 485 Seventh Avenue, 14th Floor; New York; NY; 10018; US Patent Application Number: 20030198666 Date filed: September 6, 2002 Abstract: A method of attenuating the undesirable incidence of diseases associated with chronic dosing of insulin is provided whereby the oral administration to a patient of insulin along with a suitable delivery agent that facilitates the absorption of insulin from the gastrointestinal tract of the patient in a therapeutically effective amount, for treatment of diabetes. Also disclosed are pharmaceutical dosage forms for oral administration to a patient for the treatment of diabetes, comprising insulin and a delivery agent that facilitates insulin transport in a therapeutically effective amount to the bloodstream and that result in a lower incidence of vascular diseases associated with the repeated administration of insulin. Excerpt(s): This application claims the benefit of U.S. Provisional Patents No. 60/346,746 filed Jan. 7, 2002, No. 60/347,312 filed Jan. 9, 2002, No. 60/389,364 filed Jun. 17, 2002,

284 Insulin

No. 60/368,617 filed Mar. 29, 2002 and No. 60/374,979 filed Apr. 23, 2002. This invention relates to the oral delivery of therapeutic proteins in a therapeutically effective amount to the bloodstream. This invention further relates to oral administration of proteins as active agents as part of a therapeutic regimen. This invention further relates to the oral administration of insulin in a therapeutically effective amount for the treatment of diabetes. This invention further relates to compositions of a delivery agent and insulin for oral administration that facilitates insulin transport in a therapeutically effective amount to the bloodstream for the treatment of diabetes. This invention further provides methods for the preparation of a composition comprising insulin for oral administration. The present invention further relates to methods for reducing adverse effects on the vascular system that are associated with insulin therapy. More specifically, the present invention relates to methods that reduce the incidence of diseases associated with chronic administration of insulin. The present invention is also directed to oral pharmaceutical dosage forms that are administrable on a chronic basis to diabetics, in part to achieve such results. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical composition Inventor(s): Odaka, Hiroyuki; (Kobe, JP), Sohda, Takashi; (Takatsuki, JP), Ikeda, Hitoshi; (Higashiosaka, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030216443 Date filed: June 17, 2003 Abstract: Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes. Excerpt(s): The present invention relates to a pharmaceutical composition comprising an insulin sensitivity enhancer in combination with one or more other antidiabetics differing from said enhancer in the mechanism of action. Recent years, the pathology of diabetes has become more and more understood and, in parallel, drugs specific for the respective pathologic states have been developed. Accordingly a variety of drugs having new mechanisms of action have appeared one after another. Insulin sensitivity enhancers are also known as insulin resistance deblockers because they have the action to normalize the impaired insulin receptor function, and are gathering much attention in these years. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 285

•

Pharmaceutical proteins, human therapeutics, human serum albumin, insulin, native cholera toxic b submitted on transgenic plastids Inventor(s): Daniell, Henry; (Winter Park, FL) Correspondence: Schnader Harrison Segal & Lewis; IP Department 36th Floor; 1600 Market Street; Philadelphia; PA; 19103; US Patent Application Number: 20030204864 Date filed: April 18, 2001 Abstract: Transgenic chloroplast technology could provide a viable solution to the production of Insulin-like Growth Factor I (IGF-I), Human Serum Albumin (HSA), or interferons (IFN) because of hyper-expression capabilities, ability to fold and process eukaryotic proteins with disulfide bridges (thereby eliminating the need for expensive post-purification processing). Tobacco is an ideal choice because of its large biomass, ease of scale-up (million seeds per plant), genetic manipulation and impending need to explore alternate uses for this hazardous crop. Therefore, all three human proteins will be expressed as follows: a) Develop recombinant DNA vectors for enhanced expression via tobacco chloroplast genomes b) generate transgenic plants c) characterize transgenic expression of proteins or fusion proteins using molecular and biochemical methods d) large scale purification of therapeutic proteins from transgenic tobacco and comparison of current purification/processing methods in E. coli or yeast e) Characterization and comparison of therapeutic proteins (yield, purity, functionality) produced in yeast or E. coli with transgenic tobacco f) animal testing and pre-clinical trials for effectiveness of the therapeutic proteins.Mass production of affordable vaccines can be achieved by genetically engineering plants to produce recombinant proteins that are candidate vaccine antigens. The B subunits of Enteroxigenic E. coli (LTB) and cholera toxin of Vibrio cholerae (CTB) are examples of such antigens. When the native LTB gene was expressed via the tobacco nuclear genome, LTB accumulated at levels less than 0.01% of the total soluble leaf protein. Production of effective levels of LTB in plants, required extensive codon modification. Amplification of an unmodified CTB coding sequence in chloroplasts, up to 10,000 copies per cell, resulted in the accumulation of up to 4.1% of total soluble tobacco leaf protein as oligomers (about 410 fold higher expression levels than that of the unmodified LTB gene). PCR and Southern blot analyses confirmed stable integration of the CTB gene into the chloroplast genome. Western blot analysis showed that chloroplast synthesized CTB assembled into oligomers and was antigenically identical to purified native CTB. Also, GM.sub.1,-ganglioside binding assays confirmed that chloroplast synthesized CTB binds to the intestinal membrane receptor of cholera toxin, indicating correct folding and disulfide bond formation within the chloroplast. In contrast to stunted nuclear transgenic plants, chloroplast transgenic plants were morphologically indistinguishable from untransformed plants, when CTB was constitutively expressed. The introduced gene was stably inherited in the subsequent generation as confirmed by PCR and Southern blot analyses. Incrased production of an efficient transmucosal carrier molecule and delivery system, like CTB, in transgenic chloroplasts makes plant based oral vaccines and fusion proteins with CTB needing oral administration a much more practical approach. Excerpt(s): (60/115,987) Research efforts have been made to synthesize high value pharmacologically active recombinant proteins in plants. Recombinant proteins such as vaccines, monoclonal antibodies, hormones, growth factors, neuropeptides, cytotoxins, serum proteins and enzymes have been expressed in nuclear transgenic plants (May et al., 1996). It has been estimated that one tobacco plant should be able to produce more recombinant protein than a 300-liter fermenter of E. coli. In addition, a tobacco plant

286 Insulin

produces a million seeds, thereby facilitating large-scale production. Tobacco is also an ideal choice because of its relative ease of genetic manipulation and an impending need to explore alternate uses for this hazardous crop. (60/185,987) A primary reason for the high cost of production via fermentation is the cost of carbon source co-substances as well as maintenance of a large fermentation facility. In contrast, most estimates of plant production are a thousand-fold less expensive than fermentation. Tissue specific expression of high value proteins in leaves can enable the use of crop plants as renewable resources. Harvesting the cobs, tubers, seeds or fruits for food and feed and leaves for value added products should result in further economy with no additional investment. (60/185,987) However, one of the major limitations in producing pharmaceutical proteins in plants is their low level of foreign protein expression, despite reports of higher level expression of enzymes and certain proteins. May et al. (1998) discuss this problem using the following examples. Although plant derived recombinant hepatitis B surface antigen was as effective as a commercial recombinant vaccine, the levels of expression in transgenic tobacco were low (0.01% of total soluble protein). Even though Norwalk virus capsid protein expressed in potatoes caused oral immunization when consumed as food (edible vaccine), expression levels were low (0.3% of total soluble protein). A synthetic gene coding for the human epidermal growth factor was expressed only up to 0.001% of total soluble protein in transgenic tobacco. Human serum albumin has been expressed only up to 0.02% of the total soluble protein in transgenic plants. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Phenotypic screen of chimeric proteins Inventor(s): Jang, Young-Soon; (Yuseong-gu, KR), Kim, Jin-Soo; (Yuseong-gu, KR), Lee, Dong-Ki; (Yuseong-gu, KR), Lee, Horim; (Chungcheongnam-do, KR), Lee, Seong-Il; (Yuseong-gu, KR), Lee, Yangsoon; (Yuseong-gu, KR), Park, Kyung-Soon; (Yuseong-gu, KR), Seol, Wongi; (Yuseong-gu, KR), Yang, Hyo-Young; (Yuseong-gu, KR) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030194727 Date filed: December 9, 2002 Abstract: In one aspect, a library of nucleic acids that encode different artificial, chimeric proteins is screened to identify a chimeric protein that alters a phenotypic trait of a cell or organism. The chimeric protein can be identified without a priori knowledge of a particular target gene or pathway. Some chimeric proteins include multiple zinc finger domains and can induce, for example, thermotolerance, solvent-tolerance, altered cellular growth, insulin production, differentiation, and drug resistance. Excerpt(s): This application claims the benefit of priority of U.S. Serial No. 60/338,441, filed Dec. 7, 2001; U.S. Serial No. 60/376,053, filed Apr. 26, 2002; U.S. Serial No. 60/400,904, filed Aug. 2, 2002; and U.S. Serial No. 60/401,089, filed Aug. 5, 2002, the contents of each of which is hereby incorporated by reference in their entirety for all purposes. Most genes are regulated at the transcriptional level by polypeptide transcription factors that bind to specific DNA sites within the gene, typically in promoter or enhancer regions. These proteins activate or repress transcriptional initiation by RNA polymerase at the promoter, thereby regulating expression of the target gene. Many transcription factors, both activators and repressors, include structurally distinct domains that have specific functions, such as DNA binding, dimerization, or interaction with the transcriptional machinery. The DNA binding

Patents 287

portion of the transcription factor itself can be composed of independent structural domains that contact DNA. The three-dimensional structures of many DNA-binding domains, including zinc finger domains, homeodomains, and helix-turn-helix domains, have been determined from NMR and X-ray crystallographic data. Effector domains such as activation domains or repression domains retain their function when transferred to DNA-binding domains of heterologous transcription factors (Brent and Ptashne, (1985) Cell 43:729-36; Dawson et al., (1995) Mol. Cell Biol. 15:6923-31). Artificial transcription factors can be produced that are chimeras of zinc finger domains. For example, WO 01/60970 (Kim et al.) describes methods for determining the specificity of zinc finger domains and for constructing artificial transcription factors that recognize particular target sites. One application for artificial transcription factors is to alter the expression of a particular target gene. Target sites are identified in the regulatory region of the target gene, and artificial transcription factors are engineered to recognize one or more of the target sites. When such artificial transcription factors are introduced into cells, they may bind to the corresponding target sites and modulate transcription. This strategy for controlling the expression of a target gene is sometimes referred to as the "target-driven" approach for identifying transcription factors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Polyamino acid-based particle insulin formulation Inventor(s): Andreasen, Kasper Huus; (Kobenhavn V, DK), Kimer, Lone; (Farum, DK) Correspondence: Reza Green, ESQ.; Novo Nordisk Pharmaceuticals, INC.; 100 College Road West; Princeton; NJ; 08540; US Patent Application Number: 20030211976 Date filed: March 7, 2003 Abstract: This invention relates to dual-release formulations of insulin comprising polyamino acid particles and insulin, and a method of preparing such formulations Excerpt(s): This application claims priority under 35 U.S.C. 119 of Danish application no. PA 2002 00350 filed Mar. 7, 2002 and U.S. application No. 60/353,135 filed Mar. 8, 2002, the contents of which are fully incorporated herein by reference. This invention relates to dual-release formulations of insulin comprising polyamino acid particles and insulin, and a method of preparing such formulations. Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Protein tyrosine phosphate-1B (PTP-1B) deficient mice and uses thereof Inventor(s): Elchebly, Mounib; (Montreal, CA), Gresser, Michael; (Les Cedres, CA), Kennedy, Brian; (Kirkland, CA), Payette, Paul; (St. Laurent, CA), Ramachandran, Chidambaram; (Pierrefonds, CA), Trembly, Michel; (Dorval, CA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030217379 Date filed: June 12, 2003

288 Insulin

Abstract: The present invention provides mice that have had their PTP-1B genes disrupted by targeted homologous recombination. The mice have no detectable PTP-1B protein, yet appear to be physiologically normal. However, in the fed state on a normal diet, the mice have half the level of circulating insulin as their wild-type littermates. In glucose and insulin tolerance tests, the mice show an increased insulin sensitivity. When fed a high fat, high carbohydrate diet, the mice show a resistance to weight gain as compared to their wild-type littermates. Methods of making the mice and cell lines derived from the mice are also provided. The present invention also provides methods of idendifying inhibitors of the enzymatic activity of PTP-1B as well as inhibitors identified by such methods. Excerpt(s): The invention is directed to the field of transgenic mice containing a disrupted PTP-1B gene. The mice may contain a disruption in either one or both copies of the PTP-1B gene. In the case of mice containing a disruption in both copies of the PTP-1B gene, such mice lack detectable expression of PTP-1B protein. Protein tyrosine phosphatases (PTPases) are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al., 1991, Science 253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is a.about.50 kd intracellular protein present in abundant amounts in various human tissues (Charbonneau et al., 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15). Like other PTPases, PTP-1B has a catalytic domain characterized by the sequence motif (I/V)HCXAGXXR(S/T)G (SEQ.ID.NO.:1), containing arginine and cysteine residues that are critical to the enzyme's activity (Streuli et al., 1990, EMBO J. 9:2399-2407; Guan et al., 1990, Proc. Natl. Acad. Sci. USA 87:1501-1505; Guan & Dixon, 1991, J. Biol. Chem. 266:17026-17030). The amino terminal 35 amino acid residues of PTP-1B localize the protein to the endoplasmic reticulum (Frangioni et al., 1992, Cell 68:545-560). Determining which proteins are substrates of PTP-1B has been of considerable interest. One substrate which has aroused special interest is the insulin receptor. The binding of insulin to the insulin receptor results in autophosphorylation of the receptor, most notably on tyrosines 1146, 1150, and 1151 in the kinase catalytic domain (White & Kahn, 1994, J. Biol. Chem. 269:1-4). This causes activation of the insulin receptor tyrosine kinase, which phosphorylates the various insulin receptor substrate (IRS) proteins that propagate the insulin signaling event further downstream to mediate insulin's various biological effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pulmonary administration of chemically modified insulin Inventor(s): Bueche, Blaine; (Castro Valley, CA), Harris, J. Milton; (Huntsville, AL), Kuo, Mei-Chang; (Palo Alto, CA), Leach, Chester; (El Granada, CA), Patton, John S.; (Portola Valley, CA), Perkins, Kimberly; (Belmont, CA) Correspondence: Nektar Therapeutics; 150 Industrial Road; San Carlos; CA; 94070; US Patent Application Number: 20030216542 Date filed: April 1, 2003 Abstract: The present invention provides active, hydrophilic polymer-modified derivatives of insulin. The insulin derivatives of the invention are, in one aspect, suitable for delivery to the lung and exhibit pharmakokinetic and/or pharmacodynamic properties that are significantly improved over native insulin.

Patents 289

Excerpt(s): This application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 60/292,423, the content of which is incorporated herein by reference in its entirety. The present invention is directed to bioactive, hydrophilic polymer-modified insulin derivatives for delivery to the lung by inhalation. Methods for preparing and administering such derivatives are also provided. Insulin is a polypeptide hormone that is produced in the pancreatic.beta.-cells of normal (nondiabetic) individuals. Human insulin is a 51 amino acid polypeptide hormone with a molecular weight of about 5800 daltons. The insulin molecule is composed of two peptide chains (an A and a B chain) containing one intrasubunit and two intersubunit disulfide bonds. The A chain is composed of 21 amino acids while the B chain is composed of 30 amino acids. The two chains of insulin form a highly ordered structure with several.alpha.-helical regions in both the A and the B chains. Interestingly, the isolated chains of insulin are inactive. In solution, insulin can exist as a monomer or as a dimer or as a hexamer. Insulin is hexameric in the highly concentrated preparations used for subcutaneous therapy but becomes monomeric as it is diluted in body fluids. Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels; a systemic deficiency of insulin causes diabetes. The survival of diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pyridine and quinoline derivatives Inventor(s): Boehringer, Markus; (Moehlin, CH), Loeffler, Bernd Michael; (Oberrimsingen, DE), Peters, Jens-Uwe; (Grenzach-Wyhlen, DE), Riemer, Claus; (Freiburg, DE), Weiss, Peter; (Basle, CH) Correspondence: Hoffmann-la Roche INC.; Patent Law Department; 340 Kingsland Street; Nutley; NJ; 07110 Patent Application Number: 20030195188 Date filed: February 11, 2003 Abstract: The present invention provides compounds of formula (I) 1wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance. Excerpt(s): The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular, DPP-IV efficiently and rapidly degrades glucagon-like peptide 1 (GLP-1), which is one of the most potent stimulators of insulin production and secretion. Inhibiting DPP-IV would potentiate the effect of endogenous GLP-1, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes mellitus (e.g. Vilhauer, WO98/19998). Other related state of the art can be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, U.S. Pat. No. 6,110,949, WO 00/34241 and U.S. Pat. No. 6,011,155. and pharmaceutically acceptable salts thereof. We have found novel DPP-IV inhibitors that very efficiently lower plasma glucose levels. Consequently,

290 Insulin

the compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. Surprisingly, the compounds of the present invention can also be used in the treatment and/or prophylaxis of Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity and/or metabolic syndrome. Furthermore, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension. Unexpectedly, the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared to other DPP IV inhibitors known in the art, such as e.g. in context with pharmacokinetics and bioavailability. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Substituted phenyl compounds for the treatment of non-insulin dependent diabetes mellitus Inventor(s): Caufield, Craig E.; (New York, NY), Greenfield, Alexander A.; (Princeton Junction, NJ), Morris, Koi M.; (Plainsboro, NJ), Morrison, Eamonn P.; (Yardley, PA), Sabatucci, Joseph P.; (Collegeville, PA) Correspondence: Wyeth; Patent Law Group; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030203941 Date filed: April 8, 2003 Abstract: This invention provides compounds of formula I, having the structure 1wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and B are as defined in the specification, or a pharmaceutically acceptable salt thereof, that are useful in treating metabolic disorders mediated by insulin resistance or hyperglycemia. Excerpt(s): This application claims the benefit under 35 U.S.C.sctn.119(e) to U.S. provisional application Serial No. 60/371,540 filed Apr. 10, 2002, which is hereby incorporated by reference in its entirety. This invention relates to novel compounds of general formula I or pharmaceutically acceptable salts thereof, which lower plasma glucose levels and/or insulin levels in vivo and/or inhibit the production of PEPCK enzyme and/or lower glucose and/or insulin levels in cultured cells and are therefore useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type 1), formerly referred to as juvenile onset diabetes since it was evident early in life, and non-insulin dependent diabetes mellitus (NIDDM or Type 2), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders. Insulin regulates glucose homeostasis mainly by acting on two targets tissues: liver and muscle. Liver is the only site of glucose production and skeletal muscle the main site of insulin mediated glucose uptake.

Patents 291

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Sugar decomposition inhibitor, digestive enzyme activity inhibitor, insulin secretion controller, and healthy food and beverage Inventor(s): Hayashi, Kazuhiko; (Shizuoka, JP), Kakuda, Takami; (Shizuoka, JP), Sakane, Iwao; (Shizuoka, JP), Suzuki, Yuko; (Shizuoka, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20030211176 Date filed: June 16, 2003 Abstract: A sugar decomposition inhibitor, a maltase activity inhibitor, a glucoamylase activity inhibitor, a sucrase activity inhibitor and an isomaltase activity inhibitor comprising as an effective component a hot-water extract of banaba, a synthetic resin adsorption fraction of said hot-water extract, or a mixture thereof are provided. Further, an insulin secretion controller comprising as an effective component a hot-water extract of banaba is also provided. In addition, a healthy food and beverage comprising a hotwater extract of banaba, a synthetic resin adsorption fraction of said hot-water extract or a mixture thereof and sugar except for monosaccharides are provided. Excerpt(s): The present invention relates to a sugar decomposition inhibitor, a digestive enzyme activity inhibitor, and an insulin secretion controller derived from banaba belonging to the family Lythraceae in the order Myrtaceae, and a healthy food and beverage that contains them. Banaba (Lagerstroemia speciosa L. Pers.) belongs to the family Lythraceae in the order Myrtaceae and is a kind of Lagerstroemia distributed in the Tropical Asia. Juice obtained by boiling its leaves and flowers has been drunk from the old times as a treatment medicine of diabetes in the Philippines and other countries. Recently, in Japan, its effects of treating diabetes and controlling the blood sugar level are also perceived, and the number of people who drink its component as health tea or the like is increasing. Relating to such pharmacological effects of banaba, it was already reported in the 1940's that the blood sugar level could be lowered by about 16-49 mg/dl with the dose of 1-2 g of dry leaf/kg of weight as a result of administering decoction of banaba dry leaves to normal domestic rabbits (F. Garcia: `On the hypoglycemic effect of decoction of Lagerstroemia speciosa (Banaba)` J. Philip. Med. Assoc. 20, 395 (1940)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Synergistic effect of a sulfonylurea and/or non-sulfonylurea Kchannel blocker, and a phosphodiesterase 3 type inhibitor Inventor(s): Fryburg, David A.; (East Lyme, CT), Parker, Janice C.; (Ledyard, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030216294 Date filed: June 5, 2003 Abstract: The present invention provides methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary

292 Insulin

syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also provides kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. Excerpt(s): This application is filed claiming priority to U.S. Ser. No. 09/829,874, filed Apr. 10, 2001, now allowed, which claims priority to U.S. Provisional Application Serial No. 60/196,728, filed Apr. 13, 2000. The present invention relates to methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes can be improved. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 293

•

Systemic administration of a therapeutic preparation Inventor(s): Backstrom, Kjell Goran Erik; (Lund, SE), Dahlback, Carlos Magnus Olof; (Lund, SE), Edman, Peter; (Bjarred, SE), Johansson, Ann Charlotte Birgit; (Lund, SE) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030211972 Date filed: March 27, 2003 Abstract: A method of treating a patient in need of insulin treatment, including the steps of introducing into the lower respiratory tract of the patient an effective amount of a therapeutic preparation in the form of a dry powder containing (a) insulin and (b) an enhancer compound which enhances the absorption of insulin in the lungs of the patient. Excerpt(s): This application is a continuation of U.S. Ser. No. 09/731,429, filed Dec. 6, 2000, which is a continuation of U.S. Ser. No. 09/158,554, filed Sep. 22, 1998, which is a continuation of U.S. Ser. No. 08/582,702, filed on Jan. 4, 1996, now U.S. Pat. No. 5,830,853, which is a continuation-in-part of U.S. Ser. No. 08/265,371, filed Jun. 23, 1994, now U.S. Pat. No. 5,506,203. The invention relates to the systemic administration of a therapeutic preparation of insulin. Diabetes mellitus (commonly referred to simply as diabetes) is a disease characterized by disregulation of metabolism, particularly glucose metabolism. In normal individuals, a rise in blood glucose levels (such as that which occurs immediately following eating) triggers the islet beta cells of the pancreas to secrete insulin, a peptide hormone, into the bloodstream. The insulin binds to insulin receptors located on a number of cell types, notably muscle cells, and thereby signals the cells to increase the rate of glucose uptake into the cells. As the blood glucose returns to normal pre-prandial levels, the amount of insulin in the blood also drops. In the absence of insulin, blood glucose levels would rise to dangerously high levels (a condition termed hyperglycemia), possibly resulting in death. Too much insulin causes abnormally low blood glucose levels (hypoglycemia), which is also dangerous and possibly fatal. In a normal individual, built-in feedback loops regulating the secretion of insulin and its clearance from the systemic circulation prevent both hyperglycemic and hypoglycemic conditions from occurring. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), usually begins in childhood. It is a disease affecting approximately one in 250 individuals in the United States. Type I diabetes is characterized by atrophy of the pancreatic beta cells, resulting in a decrease or cessation of insulin production, and leaving the patient dependent on exogenous insulin for survival. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Systems and methods for remotely controlling medication infusion and analyte monitoring Inventor(s): Bylund, Adam David; (Fremont, CA), Durban, William Jefferey; (Pleasanton, CA), Ebner, Manfred; (Oberursel, DE), Kraft, Ulrich; (Hofheim, DE), Long, Karen M.; (San Jose, CA), McCluskey, Joseph; (Sharon, MA), Stiene, Matthias; (Inverness, GB), Wardle, Michael D.; (San Jose, CA) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20030212379 Date filed: February 20, 2003

294 Insulin

Abstract: Devices, systems and methods are provided for remotely controlling medication delivery to a patient by means of a medication infusion pump, such as a subcutaneous infusion pump, and for remotely controlling the monitoring of one or more physiological fluid analytes such as by a percutaneous measurement device. The systems of the present invention include a medication infusion pump and a hand-held "fob" for the remote control of the infusion pump and/or measurement device. In addition to remotely controlling the insulin pump and the measurement device, the fob provides for the consolidation of blood chemistry data and insulin delivery data over a period of time and maintains such consolidated data for immediate and later retrieval by the user or a physician. The methods of the present invention allow a user to customize and optimize an insulin bolus delivery protocol, i.e., bolus volume and delivery duration, by factoring in or compensating for the user's current or substantially current blood chemistry evaluation and/or the user's anticipated and/or actual carbohydrate intake. Excerpt(s): The invention generally relates to continuous-delivery medication infusion systems and physiological fluid characteristic monitoring systems. More particularly, the invention is related to the user-interactive remote control of such continuousdelivery medication infusion systems and physiological fluid characteristic monitoring systems, as well as the integration of such physiological fluid characteristic monitoring systems within a remote control device. Medication infusion devices and physiological fluid characteristic monitoring devices are known in the medical field. One very common application of such devices is the delivery of insulin to and the monitoring of blood glucose levels of diabetics. Many advances have been made in recent years, with such device being integrated together to provide an all-in-one device which provides for the controlled delivery of insulin to the patient in accordance with real-time patient blood glucose levels and other requirements. While such highly automated devices have their advantages, many patients want more direct control over the administration of their medication. For example, a patient may want to stop the administration of medication during a dosage delivery period, even where the initial administration was initiated by the patient rather than according to a preprogrammed algorithm. Circumstances that may present such a situation include, for example, a change in the anticipated intake of carbohydrates by a diabetic, e.g., during a meal, a patient finds himself eating an amount of carbohydrates greater or less than what he or she anticipated prior to the meal. Such circumstances may require immediate modification of the then current insulin delivery parameters in effect on the pump. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Therapeutic uses of PAF-AH products in diabetes Inventor(s): Dietsch, Gregory N.; (Snohomish, WA), Peterman, Gary M.; (Seattle, WA), Yu, Albert S.; (Bothell, WA) Correspondence: Marshall, Gerstein & Borun Llp; 6300 Sears Tower; 233 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030215439 Date filed: February 24, 2003 Abstract: The present invention relates to uses of PAF-AH products to prevent or slow the progression of diabetes, particularly insulin dependent diabetes mellitus.

Patents 295

Excerpt(s): The present invention relates generally to novel therapeutic methods for preventing the progression of diabetes mellitus by administration of platelet activating factor acetylhydrolase (PAF-AH) products. Insulin-dependent diabetes mellitus, or IDDM, is a disease of metabolic dysregulation, particularly glucose metabolism dysregulation, with severe and long-term health consequences for sufferers, including vascular and neurologic complications. The predominant abnormality in patients with IDDM is a deficiency in insulin, the major anabolic hormone in humans. IDDM, also known as "Type I" or juvenile onset diabetes, affects 1 in 250 Americans, with 10,00015,000 new cases every year. Its prevalence is greatest in Caucasians, its frequency in that population being twice that among people of African and Asian ancestry. Typically, clinical onset is during childhood. The majority of sufferers are diagnosed before the age of 20, with peak onset around puberty; fewer than 10% of cases first appear in patients over the age of 50. The survival of patients suffering from IDDM depends entirely on the intake of exogenous insulin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of diabetes and diabetic complications with NHE-1 inhibitors Inventor(s): Tracey, W. Ross; (Niantic, CT), Treadway, Judith L.; (Mystic, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030212104 Date filed: May 1, 2003 Abstract: This invention relates to methods of treating or preventing type 2 diabetes, diabetic neuropathy, diabetic cardiomyopathy, cataracts, diabetic retinopathy, foot ulcers, diabetic microangiopathy, diabetic macroangiopathy, diabetic ischemia reperfusion injury, diabetic cardiac ischemia reperfusion injury and/or insulin resistance syndrome (IRS) in mammals, particularly in humans, by administering a sodium-hydrogen exchanger type 1 (NHE-1) inhibitor or a pharmaceutical composition containing such an inhibitor. This invention also relates to combinations comprising NHE-1 inhibitors and a second pharmaceutical agent, said combinations being useful in treating type 2 diabetes, IRS, diabetic neuropathy, diabetic cardiomyopathy, cataracts, diabetic retinopathy, foot ulcers, diabetic ischemia reperfusion injury, diabetic cardiac ischemia reperfusion injury, diabetic microangiopathy and/or diabetic macroangiopathy. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/380,028 filed May 2, 2002. (1) Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which arises when patients lack insulin-producing.beta.-cells in their pancreatic glands, and (2) Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with, inter alia, impaired.beta.-cell function. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

296 Insulin

•

Treatment of insulin resistance Inventor(s): Olefsky, Jerrold M.; (Solana Beach, CA), Pillay, Tahir S.; (San Diego, CA) Correspondence: Lisa A. Haile, J.D., PH.D.; Gray Cary Ware & Freidenrich Llp; Suite 1100; 4365 Executive Drive; San Diego; CA; 92121-2133; US Patent Application Number: 20030211540 Date filed: January 28, 2003 Abstract: Methods and compositions are provided for the treatment of insulin-resistance through the inhibition of protein kinase C-mediated phosphorylation of the amino acid residue Ser.sub.1270 of the insulin receptor. Methods for testing candidate compounds suitable for inhibition of serine-phosphorylation by protein kinase C are also provided. Excerpt(s): This invention relates to methods and compositions for the treatment of insulin resistance. Insulin resistance is associated with several disease conditions including non-insulin dependent diabestes mellitus (NIDDM), obesity, hypertension, and cardiovascular disease. The most well-studies of these conditions is NIDDM. NIDDM, also termed maturity-onset diabetes or type II diabetes to differentiate it from insulin-dependent diabetes mellitus (IDDM, also termed type I or juvenile diabetes), usually occurs in middle-aged obese people and accounts for 80% to 90% of diagnosed diabetes. In addition to insulin resistance, NIDDM is associated with normal to elevated levels of insulin, hyperglycemia, increased levels of very low density lipoproteins (VLDL), and decreased muscle uptake of glucose. NIDDM is often associated with hypertriglyceridemia. Ketoacidosis, characteristic of IDDM, is not associated with NIDDM except when the patient is subjected to extreme stress (e.g., septic shock or myocardial infarction). NIDDM patients tend to develop many of the same complications associated with IDDM including nerve, eye, kidney, and coronary artery disease. Mounting scientific evidence suggests that NIDDM results from a combination of two components: 1) a hereditary, genetic component (Rotter et al. In:: Rifkin et al., Diabetes Mellitus: Theory and Practice., New York, Elsevier, 1990, pp. 378-413); and 2) an acquired component (Seely et al. In: Moller, Ed. Insulin Resistance and Its Clinical Disorders. England, John Wile & Sons, Ltd., 1993, pp. 187-252; Olefsky In: Efendic, et al. Eds. New Concepts in the Pathogenesis of NIDDM. New York, Plenum Publishing Corp., 1993; Olefsky, In: DeGroot, et al., Eds. DeGroot Textbook of Endocrinology., 3rd Ed., Philadelphia, W. B. Saunders and Co., 1994). The genetic component of NIDDM is responsible for the first stage of the disease, termed the "prediabetic" state. The prediabetic state is characterized by hyperinsulinemia and "primary" insulin resistance. Insulin responsiveness in the prediabetic state is sufficient to maintain normal glucose tolerance (NGT) or at least impaired glucose tolerance (IGT). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia Inventor(s): Luo, Jian; (Brisbane, CA), Luskey, Kenneth L.; (Saratoga, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030220399 Date filed: March 4, 2003

Patents 297

Abstract: The present invention provides the use of (-) (3-trihalomethylphenoxy) (4halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/703,487 filed Oct. 31, 2000 which is a continuation of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999; this application is a continuation-in-part of U.S. patent application Ser. No. 09/585,907 filed on Jun. 2, 2000 which is a continuation-in-part of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999; this application is a continuation-in-part of U.S. patent application Ser. No. 09/724,788 filed Nov. 28, 2000 which is a continuation in part of U.S. patent application Ser. No. 09/585,907 filed on Jun. 2, 2000 which is a continuation-in-part of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999. The contents of these priority applications are each herein individually incorporated by reference for all purposes. The present invention relates to the use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996), and all references cited therein. According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of amp kinase activators for treatment type 2 diabetes and insulin resistance Inventor(s): Winder, William W; (Provo, UT) Correspondence: Madson & Metcalf; Gateway Tower West; Suite 900; 15 West South Temple; Salt Lake City; UT; 84101 Patent Application Number: 20030212013 Date filed: December 3, 2002 Abstract: A method of treating type 2 diabetes in a mammal is provided. The method includes the step of administering a therapeutically effective amount of an AMPactivated protein kinase activator to the mammal. The mammal may be for example, a human, a rat, a mouse, and the like. The AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal. The activation of the AMP-activated protein kinase activator can produce the benefits of exercise training including the translocation of GLUT4 in the muscle cells of the mammal. A method of treating insulin resistance in a mammal is also provided. To treat the insulin resistance a therapeutically effective amount of an AMP-activated protein kinase activator is given to the mammal. Excerpt(s): This application is related to and claims the benefit of U.S. Provisional Application Serial No. 60/212,476 of William W. Winder filed Jun. 16, 2000 and entitled

298 Insulin

"Use of AMP Kinase Activators for Treatment of Type 2 Diabetes," which is incorporated herein by this reference. The present invention relates to the methods of treatment of type 2 diabetes and insulin resistance. More specifically, the invention relates to methods of treatment of type 2 diabetes and insulin resistance through artificial activation of AMP kinase. Type 2 diabetes is characterized by relative insensitivity to the actions of insulin on glucose uptake. American Diabetes Association: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes 1998; 21:S5-S19, 1998; Ferrannini, E Endocr Rev 19:477-490 (1997); Gerich, J E Endocr Rev 19:491-503 (1997). In the early stages of this disease, increased insulin secretion can compensate for the insensitivity, but in later stages, insulin deficiency can occur resulting in marked hyperglycemia. Patients with Type 2 diabetes also have dyslipidemia and increased hepatic glucose production. In order to understand the insulin-insensitivity, it is important to understand the basic mechanisms for glucose uptake into the muscle cell, since skeletal muscle represents a large proportion of the insulin-sensitive tissue in the body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with insulin, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “insulin” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on insulin. You can also use this procedure to view pending patent applications concerning insulin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

299

CHAPTER 7. BOOKS ON INSULIN Overview This chapter provides bibliographic book references relating to insulin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on insulin include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “insulin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on insulin: •

Outsmarting Diabetes: A Dynamic Approach for Reducing the Effects of InsulinDependent Diabetes Source: Minneapolis, MN: Chronimed Publishing. 1994. 247 p. Contact: Available from Chronimed Publishing. P.O. Box 59032, Minnetonka, MN 55459-9686. (800) 848-2793 or (612) 541-0239. Fax (800) 395-3344 or (612) 541-0210. PRICE: $14.95. ISBN: 1565610512. Available from Joslin Publications. One Joslin Place, Boston, MA 02215. (800) 344-4501. Fax (617) 732-2562. PRICE: $14.95. Summary: Based on the results of the Diabetes Control and Complications Trial (DCCT) and the expertise of the Joslin Diabetes Center in Boston, this book explains to readers the benefits of careful diabetes control. Designed to help people with diabetes reduce their risks for complications, the book's 11 chapters address whether or not complications can truly be prevented; intensive insulin management; designing an individualized plan; getting started; maintenance on an intensive plan; meal planning;

300 Insulin

using multiple daily insulin injections; using insulin pumps; exercise and the intensive plan; pregnancy and intensive diabetes therapy; psychological concerns; and handling problems. Numerous appendices provide information on intensified conventional treatment programs; Ultralenta programs; the use of premeal regular plus bedtime intermediate insulin; the insulin pump; calculating daily volume for insulin pump therapy; exercise guidelines; hyperglycemia; hypoglycemia; products and foods for hypoglycemic reactions; and a sample record book. A brief subject index concludes the volume. •

Understanding Insulin-Dependent Diabetes. 8th ed Source: Denver, CO: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center. Children's Diabetes Foundation at Denver. 1995. 253 p. Contact: Available from Guild of the Children's Diabetes Foundation at Denver. 777 Grant Street, Suite 302, Denver, CO 80203. (800) 695-2873 or (303) 863-1200. Fax (303) 863-1122. PRICE: $10.00. The book is also available at http://www.uchsc.edu/misc/diabetes/bdc.html. Summary: Designed for the families of children with diabetes, this book uses the Pink Panther character to explain diabetes and its care. The book begins by explaining the importance of education in diabetes, what diabetes is, and the causes of diabetes. Urine ketone testing, hypoglycemia, blood sugar testing, insulin, nutrition, blood sugar control, complications, sick day and surgery management, intensive diabetes management, research, ketonuria, and ketoacidosis are explained in depth. Many chapters of the book discuss the social and emotional aspects of coping with diabetes, including family concerns, responsibilities of children at different ages, the challenges of being a teenager with diabetes, school, babysitters, vacations, and camp. 3 appendices and a subject index conclude the book. Charts, tables, and illustrations are used throughout the book. The book is written at a 10th to 12th grade level.

•

Insulin Resistance Source: Malden, MA: Blackwell Science, Inc. 2002. 190 p. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $49.95. ISBN: 0632056622. Summary: Insulin resistance, defined as a reduced biological action of insulin, has emerged as a major factor in the development and progression of a number of common noncommunicable diseases in humans. The role of insulin resistance in the etiology of type 2 diabetes is particularly well established. However, insulin resistance has also come to be regarded as a key component of a broader syndrome of common metabolic defects that conspire to increase the risk of atherosclerotic coronary heart disease. This book summarizes the current state of knowledge about insulin resistance, a condition that embraces many different medical specialties. Three sections cover the pathophysiology of insulin resistance, insulin resistance in clinical medicine, and the management of insulin resistance and associated conditions. Key points are highlighted in the margins of the text and chapters include tables and illustrations; reference lists are provided at the end of each major section. A subject index concludes the handbook.

Books

•

301

Practical Insulin: A Handbook for Prescribers Source: Alexandria, VA: American Diabetes Association. 2002. 59 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $7.95 plus shipping and handling. ISBN: 1580401538. Summary: The medical practice of many physicians now includes handling everincreasing numbers of patients with diabetes. Insulin therapy is a medical necessity for all patients with type 1 diabetes and the many patients with type 2 diabetes who cannot reach their glycemic (levels of blood glucose) without insulin therapy. This handbook offers solutions to the many common challenges involved in prescribing insulin, from choosing insulin regimens, to dealing with patient reluctance to start insulin therapy, to minimize the weight gain that often accompanies improved glycemic control. Specific topics include patient selection, insulin choices, the different types of insulin and their character, mixing insulins, insulin regimens (for type 1 and for type 2 patients), troubleshooting, patient SMBG (self monitoring of blood glucose) records, and patient education. The handbook also includes numerous appendices: endogenous insulin action, insulin storage, insulin potency, additives, insulin delivery, insulin pump, and determining insulin-to-CHO (carbohydrates) ratio. The author notes that there are no standards for how to best use insulin therapy; individual patient strategies must be implemented. 11 figures. 11 tables.

•

Diabetes 101: A Pure and Simple Guide for People Who Use Insulin. 3rd ed Source: Minneapolis, MN: Chronimed Publishing. 1998. 202 p. Contact: Available from Chronimed Publishing. P.O. Box 59032, Minnetonka, MN 55459-9686. (800) 848-2793 or (612) 541-0239. Fax (800) 395-3344 or (612) 541-0210. PRICE: $12.95 plus shipping and handling. ISBN: 156561156x. Summary: This book is a brief and readable guide to important basic information needed every day by people who take insulin to control their diabetes. Written in story format, the book uses real life examples to explore topics including diabetes care and supplies, insurance coverage, and reimbursement; ways to prevent and cope with stress; avoiding insulin reactions; self monitoring of blood glucose; sick days; and current advances in diabetes research. A subject index concludes the volume.

•

Sun, the Rain, and the Insulin: Growing Up with Diabetes Source: Orono, ME: Tiffin Press of Maine. 1996. 250 p. Contact: Available from Tiffin Press of Maine. P.O. Box 549, Orono, ME 04473. PRICE: $12.95 plus $2.55 shipping and handling. ISBN: 0964601850. Summary: This book is based on the actual experiences of participants at Camp Kee-ToKin. This first diabetes family camp, located at Hersey Retreat in Maine, was initiated by the author and a diabetes nurse educator in 1982. Eighteen chapters provide information on family concerns, which include compliance issues, rebellion, immaturity, and rejection of diabetes by both children and parents. Characters include the members of six participating families, two counselors, the camp doctor, diabetes nurse educator, dietitian, psychologist, and cook. According to the foreword, approximately 250,000 children and adolescents in the United States have insulin-dependent diabetes mellitus (IDDM, or Type I), and there is evidence that this number is increasing. A list of

302 Insulin

characters and a map of Hersey Retreat precedes the chapters. The book concludes with an epilogue, photographs of campers, a glossary, a list of other books on diabetes, and a list of resource and support organizations. (AA-M). •

Insulin Pump Therapy Book: Insights from the Experts Source: Sylmar, CA: MiniMed Technologies. 1995. 162 p. Contact: Available from MiniMed Technologies. 12744 San Fernando Road, Sylmar, CA 91342. (800) 933-3322 or (818) 362-5958. Fax (818) 364-2246. PRICE: $19. ISBN: 0964783703. Summary: This book provides readers with a comprehensive overview of the insulin pump. The authors hope to help establish insulin pump therapy as a cost-effective mode of intensive diabetes management that not only facilitates normalized blood glucose, but also makes it feasible for people living with diabetes to experience the most normal lifestyle possible. Thirteen chapters the benefits of insulin pump therapy; candidate selection; initiating pump therapy; establishing and verifying basal rates; bolus and supplemental insulin; counting carbohydrates; pattern analysis and recordkeeping; everyday management; exercise and the pump; preventing diabetic ketoacidosis (DKA); hypoglycemia and its prevention; and pump therapy in preconception and pregnancy. A subject index concludes the volume.

•

Pumping Insulin: Everything in a Book for Successful Use of an Insulin Pump. 2nd ed Source: San Diego, CA: Torrey Pines Press. 1994. 156 p. Contact: Available from Torrey Pines Press. 1030 West Upas Street, San Diego, CA 92103-3821. (619) 497-0900. Fax (619) 497-0900. PRICE: $19.95; discounts available for larger quantities. ISBN: 1884804772. Summary: This book serves as an instructional manual for people who use insulin pumps to help manage their diabetes. Designed to be used as an addition to a physician's guidance, the book offers a comprehensive approach to obtaining the best results from an insulin pump and presents detailed suggestions for dealing with problem areas in blood glucose control. Twenty one chapters discuss the education and preparation necessary before obtaining an insulin pump; learning to use the pump; and troubleshooting. Each chapter includes an outline of the points presented and numerous charts and worksheets to illustrate the main concepts. An appendix presents a guide to carbohydrate factors and carbohydrate countin g.

•

Insulin Resistance: The Metabolic Syndrome X Source: Totowa, NJ: Humana Press, Inc. 1999. 384 p. Contact: Available from Humana Press, Inc. Customer Service, 999 Riverview Drive, Suite 208, Totowa, NJ 07512. (973) 256-1699. Fax (973) 256-8341. E-mail: [email protected]. PRICE: $145.00 plus shipping and handling. ISBN: 0896035883. Summary: This book summarizes the current understanding of how insulin resistance and its compensating hyperinsulinemia play a role in the pathogenesis and clinical course of high blood pressure, cardiovascular disease, and polycystic ovary disease. Part one focuses on genetic and lifestyle factors that contribute to the differences in insulin action that exist in the population at large. Topics include the genetic determinants of

Books

303

insulin resistance, ethnic variation in insulin resistance and risk of type 2 diabetes, fetal effects on insulin resistance and glucose tolerance, obesity and insulin resistance, the role of body fat distribution in insulin resistance, physical activity and insulin resistance in humans, and insulin resistance in smokers and other long-term users of nicotine. Part two focuses on the pathophysiologic consequences of insulin resistance and the efforts made to compensate for this defect to prevent decompensation of glucose homeostasis. Topics include insulin resistance and inhibitors of insulin receptor tyrosine kinase, nuclear magnetic resonance studies on the mechanism of insulin resistance, skeletal muscle insulin resistance in humans, the role of the liver in insulin action and resistance, the pathophysiological consequences of adipose tissue insulin resistance, and insulin action and endothelial function. Part three considers the clinical syndromes excluding type 2 diabetes, that are related to insulin resistance. Topics include the implications of insulin resistance and dyslipidemia for coronary heart disease risk; insulin resistance and blood pressure; microalbuminuria and insulin resistance; plasminogen activation inhibitor, obesity, and insulin resistance; insulin resistance and cardiovascular disease; and insulin resistance effects on sex hormones and ovulation in the polycystic ovary syndrome. Numerous figures. 31 tables. Numerous references. •

Insulin-Dependent Diabetes in Children, Adolescents and Adults: How to Become an Expert on Your Own Diabetes Source: Uddevalla, Sweden: Becton Dickinson and Company. 1998. 268 p. Contact: Available from Becton Dickinson and Company. Becton Dickinson Division, 1 Becton Drive, Franklin Lakes, NJ 07417-1884. (201) 847-6800. Fax (201) 847-6692. PRICE: $29.00; plus shipping and handling. ISBN: 9163062615. Also available from www.amazon.com and Piara Publishing. Turkosv 12, S-451 62 Uddevalla, Sweden. +46 522 66 93 66. E-mail: [email protected]. Summary: This illustrated book provides people with the practical information they need to take good care of their diabetes. The book begins by describing the anatomy of the digestive system and explaining how the healthy body works. This is followed by sections that focus on self care; the symptoms and treatment of hypoglycemia and hyperglycemia; insulin treatment; insulin requirements; injection technique; injection aids such as indwelling catheters, automatic injectors, and jet injectors; the insulin pump; the side effects of insulin treatment; the adjustment of insulin doses; temporary and permanent changes to insulin doses; and urine and blood testing. Other sections focus on diet, the use of dietary sweeteners, the consumption of candy and ice cream, weight control, eating disorders, physical exercise, stress, sick days, active and passive smoking, alcohol consumption, pregnancy, social issues, travel, associated diseases, and complications. Several sections focus on research efforts, including research addressing the issue of whether better blood glucose control can lessen the risk of complications and research concerning equipment improvements, the cause of diabetes, and alternative modes of insulin administration. Remaining sections deal with psychological issues, needle phobia, and well known persons who have diabetes. The book includes a glossary, an index, and a reading list. 433 references.

•

Instructional Aid on Insulin-Dependent Diabetes Mellitus. 10th ed Source: Austin, TX: Designer's Ink. 1996. 252 p. Contact: Available from Designer's Ink. P.O. Box 200633, Austin, TX 78720-0633. (512) 832-0611. PRICE: $21.00 (as of 1996). ISBN: 0963618806.

304 Insulin

Summary: Written for older children, this manual explains diabetes and teaches techniques of self care. Its question-and-answer format contributes to ease of understanding. Red, green, and black print and the use of numerous illustrations emphasize and clarify important points. Each section is followed by a quiz designed to clarify points in the text. The manual covers glucose/insulin metabolism; self-care issues such as urine testing, types of insulin and injection techniques; recognizing and handling insulin reaction and ketoacidosis; exercise and sports; camps and organizations; and psychosocial issues. A brief section offers advice for parents of a child who has diabetes. The book is available in English or Spanish.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “insulin” at online booksellers’ Web sites, you may discover nonmedical books that use the generic term “insulin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “insulin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

10th International Symposium on Endocrinology and Development: Growth and Metabolism: Obesity, Insulin Action and Use of Anthropometry by A. Attanasio (Editor) (1993); ISBN: 3805558848; http://www.amazon.com/exec/obidos/ASIN/3805558848/icongroupinterna

•

2003 Insulin Pump Weekly Calendar by Karen Dawn, Resa Levetan; ISBN: 1588082164; http://www.amazon.com/exec/obidos/ASIN/1588082164/icongroupinterna

•

Biotechnology of Insulin Therapy by J. C. Pickup (1991); ISBN: 0632030380; http://www.amazon.com/exec/obidos/ASIN/0632030380/icongroupinterna

•

Bittersweet: Diabetes, Insulin, and the Transformation of Illness by John Christopher Feudtner, Chris Feudtner; ISBN: 0807827916; http://www.amazon.com/exec/obidos/ASIN/0807827916/icongroupinterna

•

Blood Sugar Blues : Overcoming the Hidden Dangers of Insulin Resistance by Miryam Ehrlich Williamson, R. Paul St. Amand M.D. (2001); ISBN: 0802776108; http://www.amazon.com/exec/obidos/ASIN/0802776108/icongroupinterna

•

Clinician's Guide to Non-Insulin-Dependent Diabetes Mellitus: Pathogenesis and Treatment by Gerald M. Reaven; ISBN: 0824780833; http://www.amazon.com/exec/obidos/ASIN/0824780833/icongroupinterna

•

Clinician's Manual on Insulin Resistance: The Dysmetabolic Syndrome by H. E. Lebovitz (2002); ISBN: 1858739373; http://www.amazon.com/exec/obidos/ASIN/1858739373/icongroupinterna

•

Coping with Life on Insulin by Judith M. Steel, Margaret Dunn; ISBN: 0550205144; http://www.amazon.com/exec/obidos/ASIN/0550205144/icongroupinterna

•

Current Directions in Insulin-Like Growth Factor Research (Advances in Experimental Medicine and Biology, 343) by Derek Leroith, Mohan K. Raizada (Editor)

Books

305

(1994); ISBN: 0306446227; http://www.amazon.com/exec/obidos/ASIN/0306446227/icongroupinterna •

Diabetes Management in the '80s : The Role of Home Blood Glucose Monitoring and New Insulin Delivery Systems by C. M. Peterson (Author) (1982); ISBN: 0275913775; http://www.amazon.com/exec/obidos/ASIN/0275913775/icongroupinterna

•

Diabetes Sourcebook: Basic Consumer Health Information About Type 1 Diabetes (Insulin-Dependent or Juvenile-Onset Diabetes), Type 2 Diabetes (NoninsulinDependent or (Health Reference Series) by Dawn D. Matthews (Editor), Roger C. Duvoisin (2003); ISBN: 0780806298; http://www.amazon.com/exec/obidos/ASIN/0780806298/icongroupinterna

•

Diabetes Sourcebook: Basic Consumer Health Information About Type 1 Diabetes (Insulin-Dependent or Juvenile-Onset Diabetes), Type 2 Diabetes (NoninsulinDependent or adult (Health Reference Series, Vol 3) by Karen Bellenir (Editor) (1998); ISBN: 0780802241; http://www.amazon.com/exec/obidos/ASIN/0780802241/icongroupinterna

•

Diabetes Sourcebook: Basic Information About Insulin-Dependent and NoninsulinDependent Diabetes Mellitus, Gestational Diabetes, and Diabetic Complications Symptoms (Health Reference, Vol 3) by Karen Bellenir (Editor), Peter D. Dresser (Editor) (1995); ISBN: 1558887512; http://www.amazon.com/exec/obidos/ASIN/1558887512/icongroupinterna

•

Diabetes Teaching Guide for People Who Use Insulin (Diabetes Teaching Guide Series) by Hugo J. Hollerorth (1992); ISBN: 1879091003; http://www.amazon.com/exec/obidos/ASIN/1879091003/icongroupinterna

•

Diabetes Treated with Insulin: A Short Guide by Hugo J. Hollerorth, Sandy Schafer (Illustrator) (1992); ISBN: 187909102X; http://www.amazon.com/exec/obidos/ASIN/187909102X/icongroupinterna

•

Diabetes Treatment With Implantable Insulin Infusion Systems by Karl Irsigler, et al (1984); ISBN: 3541124113; http://www.amazon.com/exec/obidos/ASIN/3541124113/icongroupinterna

•

Diabetic's Jet Ejectors: Diabetic's Gun for Insulin Ejection by C. Anthony Chimpa, et al; ISBN: 0922958033; http://www.amazon.com/exec/obidos/ASIN/0922958033/icongroupinterna

•

Dietary Lipids and Insulin Action: Second International Smolenice Insulin Symposium (Annals of the New York Academy of Sciences, Vol 683) by I. Klimes, et al (1993); ISBN: 0897667980; http://www.amazon.com/exec/obidos/ASIN/0897667980/icongroupinterna

•

Discoverer of Insulin: Dr. Frederick G. Banting by Israel E. Levine; ISBN: 0671326007; http://www.amazon.com/exec/obidos/ASIN/0671326007/icongroupinterna

•

Endocrine and Metabolic Disorders Sourcebook: Basic Information for the Layperson About Pancreatic and Insulin-Related Disorders Such As Pancreatis, Diabetes, and Hypoglycemia (Health Reference Series, Vol 36) by Linda M. Shin (Editor), Linda M. Ross (Editor) (1998); ISBN: 0780802071; http://www.amazon.com/exec/obidos/ASIN/0780802071/icongroupinterna

•

Epidemiology and Etiology of Insulin-Dependent Diabetes in the Young (Pediatric and Adolescent Endocrinology, Vol 21) by C. Levy-Marchal, R. Czernichow (Editor) (1992); ISBN: 3805555210; http://www.amazon.com/exec/obidos/ASIN/3805555210/icongroupinterna

306 Insulin

•

Frederick Banting and the Discovery of Insulin (Unlocking the Secrets of Science) by John Bankston; ISBN: 1584150947; http://www.amazon.com/exec/obidos/ASIN/1584150947/icongroupinterna

•

From Oysters to Insulin: Nature and Medicine at Odds by Stephen L. DeFelice; ISBN: 0806509953; http://www.amazon.com/exec/obidos/ASIN/0806509953/icongroupinterna

•

Frontiers of Insulin Secretion by P.R. Flatt (Editor), S. Lenzen (Editor) (1995); ISBN: 1854631047; http://www.amazon.com/exec/obidos/ASIN/1854631047/icongroupinterna

•

Functional Insulin Treatment: Principles, Teaching Approach and Practice by Kinga Howorka (1996); ISBN: 3540603522; http://www.amazon.com/exec/obidos/ASIN/3540603522/icongroupinterna

•

Growth Hormone and Insulin-Like Growth Factor I in Human and Experimental Diabetes (1993); ISBN: 9992872802; http://www.amazon.com/exec/obidos/ASIN/9992872802/icongroupinterna

•

Human Insulin by Tryptic Transpeptidations of Porcine Insulin and Biosynthetic Procursors by Jan Markussen (1987); ISBN: 0746200587; http://www.amazon.com/exec/obidos/ASIN/0746200587/icongroupinterna

•

Human Insulin: Clinical Pharmacological Studies in Normal Man by D. R. Owens (1987); ISBN: 0852009518; http://www.amazon.com/exec/obidos/ASIN/0852009518/icongroupinterna

•

Immunogenetics of Insulin-Dependent Diabetes by A.H. Barnett (Editor) (1988); ISBN: 0852008406; http://www.amazon.com/exec/obidos/ASIN/0852008406/icongroupinterna

•

Immunopathology of insulin: clinical and experimental studies by K. Federlin; ISBN: 0387054081; http://www.amazon.com/exec/obidos/ASIN/0387054081/icongroupinterna

•

Instructional Aid on Insulin Dependent Diabetes Mellitus by Luther B. Md. Travis; ISBN: 0963618806; http://www.amazon.com/exec/obidos/ASIN/0963618806/icongroupinterna

•

Insulin (1990); ISBN: 3540503196; http://www.amazon.com/exec/obidos/ASIN/3540503196/icongroupinterna

•

Insulin (Handbook of Experimental Pharmacology Vol 92) by Pedro Cuatrecasas (Editor), et al (1990); ISBN: 0387503196; http://www.amazon.com/exec/obidos/ASIN/0387503196/icongroupinterna

•

Insulin Action (Developments in Molecular and Cellular Biochemistry, 24) by Ashok K. Srivastava (Editor), Barry I. Posner (Editor) (1998); ISBN: 0792381130; http://www.amazon.com/exec/obidos/ASIN/0792381130/icongroupinterna

•

Insulin Action and Diabetes (Progress in Endocrine Research and Therapy, Vol 4) by H. Joseph Goren, et al (1988); ISBN: 0881674486; http://www.amazon.com/exec/obidos/ASIN/0881674486/icongroupinterna

•

Insulin and the Cell Membrane: Proceedings by Iwar Klimes, et al; ISBN: 3718605031; http://www.amazon.com/exec/obidos/ASIN/3718605031/icongroupinterna

Books

307

•

Insulin Dependent Diabetes My First Fifty Years by John R. Bennett (2002); ISBN: 140333949X; http://www.amazon.com/exec/obidos/ASIN/140333949X/icongroupinterna

•

Insulin Pump 2002 Calendar by Karen Dawn, Resa Levetan; ISBN: 1588080536; http://www.amazon.com/exec/obidos/ASIN/1588080536/icongroupinterna

•

Insulin Resistance by Andrew J. Krentz; ISBN: 0632056622; http://www.amazon.com/exec/obidos/ASIN/0632056622/icongroupinterna

•

Insulin Resistance by David E. Moller (Editor); ISBN: 0471939773; http://www.amazon.com/exec/obidos/ASIN/0471939773/icongroupinterna

•

Insulin Resistance : Insulin Action and its Disturbances in Disease by Sudhesh Kumar (Editor), Steven O'Rahilly (Editor) (2004); ISBN: 0470850086; http://www.amazon.com/exec/obidos/ASIN/0470850086/icongroupinterna

•

Insulin Resistance and Cardiovascular Disease by S. O'Rahilly (1999); ISBN: 1901978095; http://www.amazon.com/exec/obidos/ASIN/1901978095/icongroupinterna

•

Insulin Resistance in Human Disease: Proceedings of the 7th Korea-Japan Symposium on Diabetes Mellitus, Seoul, Korea, 13-14 April 1993 (Internationa) by Kap Bum Huh, et al; ISBN: 0444816046; http://www.amazon.com/exec/obidos/ASIN/0444816046/icongroupinterna

•

Insulin Therapy by Jack L. Leahy (Editor), William T. Cefalu (Editor) (2002); ISBN: 0824707117; http://www.amazon.com/exec/obidos/ASIN/0824707117/icongroupinterna

•

Insulin, IGFS and Growth Hormone: From Basic Research to Novel Clinical Applications by P. Saenger (Editor), et al (1994); ISBN: 3805560036; http://www.amazon.com/exec/obidos/ASIN/3805560036/icongroupinterna

•

Insulin/Sulphonylurea: Combination Therapy in Type II Diabetes/2nd Symposium on Insulin/Sulphonylurea Combination Therapy in Type II Diabetes, Munic by W. Bachmann, et al (1988); ISBN: 3805548621; http://www.amazon.com/exec/obidos/ASIN/3805548621/icongroupinterna

•

Insulin: Its Receptor and Diabetes (Receptors and Ligands in Intercellular Communication, Vol 6) by Morley D. Hollenberg (Editor) (1985); ISBN: 0824773837; http://www.amazon.com/exec/obidos/ASIN/0824773837/icongroupinterna

•

Insulin: Like Growth Factors, Somatomedins by E. Martin Spencer (Editor) (1983); ISBN: 3110095629; http://www.amazon.com/exec/obidos/ASIN/3110095629/icongroupinterna

•

Insulin: Molecular Biology to Pathology by Frances M. Ashcroft (Editor), Stephen J.H. Ashcroft (Editor); ISBN: 0199632286; http://www.amazon.com/exec/obidos/ASIN/0199632286/icongroupinterna

•

Insulin-Dependent Diabetes in Children, Adolescents and Adults - How to become an expert on your own diabetes by Ragnar Hanas (1998); ISBN: 9163062615; http://www.amazon.com/exec/obidos/ASIN/9163062615/icongroupinterna

•

Insulin-Like Growth Factors (Molecular Biology Intelligence Unit) by Derek Leroith, et al (2003); ISBN: 0306478463; http://www.amazon.com/exec/obidos/ASIN/0306478463/icongroupinterna

308 Insulin

•

Insulin-like Growth Factors: Molecular and Cellular Aspects by Derek Leroith (Editor), et al; ISBN: 0849357128; http://www.amazon.com/exec/obidos/ASIN/0849357128/icongroupinterna

•

Intensive Insulin Therapy by David S. Schade; ISBN: 0874885655; http://www.amazon.com/exec/obidos/ASIN/0874885655/icongroupinterna

•

Knowing About Diabetes: For Non-Insulin-Dependent Diabetics by P. H. Wise; ISBN: 057202021X; http://www.amazon.com/exec/obidos/ASIN/057202021X/icongroupinterna

•

Lessons from Animal Diabetes VI: 75th Anniversary of the Insulin Discovery by Eleazar Shafrir (1996); ISBN: 3764338768; http://www.amazon.com/exec/obidos/ASIN/3764338768/icongroupinterna

•

Lipids and Insulin Resistance: The Role of Fatty Acid Metabolism and Fuel Partitioning (Annals of the New York Academy of Sciences, V. 967) by International Smolenice Insulin Symposium on "Lipids and Insulin Resis, Iwar Klimes (2002); ISBN: 1573313696; http://www.amazon.com/exec/obidos/ASIN/1573313696/icongroupinterna

•

Lipids and Syndromes of Insulin Resistance: From Molecular Biology to Clinical Medicine (Annals of the New York Academy Ofsciences, Vol. 827) by I. Klimes (Editor), et al (1997); ISBN: 1573310700; http://www.amazon.com/exec/obidos/ASIN/1573310700/icongroupinterna

•

Living with Diabetes : The Diabetes UK Guide for those Treated with Insulin by John L. Day (Author) (2002); ISBN: 0470845260; http://www.amazon.com/exec/obidos/ASIN/0470845260/icongroupinterna

•

Living With Diabetes: The British Diabetic Association Guide for Those Treated With Insulin by John L. Day; ISBN: 0471972746; http://www.amazon.com/exec/obidos/ASIN/0471972746/icongroupinterna

•

Magnesium and the Insulin Resistance Syndrome (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1088) by Arvo Hanni (2001); ISBN: 915545142X; http://www.amazon.com/exec/obidos/ASIN/915545142X/icongroupinterna

•

Margaret and Charley: The Personal Story of Dr. Charles Best, the Co-Discoverer of Insulin by Henry B. M. Best; ISBN: 1550023993; http://www.amazon.com/exec/obidos/ASIN/1550023993/icongroupinterna

•

Medical Management of Non-Insulin-Dependent Diabetes (Type II Diabetes) by Philip Raskin (Editor), et al; ISBN: 0945448376; http://www.amazon.com/exec/obidos/ASIN/0945448376/icongroupinterna

•

Modern Concepts of Insulin-Like Growth Factors: Proceedings of the Second International Symposium on Insulin-Like Growth Factors/Somatomedins Held ja by E. Martin Spencer (Editor); ISBN: 0444016171; http://www.amazon.com/exec/obidos/ASIN/0444016171/icongroupinterna

•

Molecular and Cellular Biology of Insulin-Like Growth Factors and Their Receptors by Derek Leroith, et al (1990); ISBN: 0306432544; http://www.amazon.com/exec/obidos/ASIN/0306432544/icongroupinterna

•

Molecular Basis of Insulin Action by Michael P. Czech (Editor) (1985); ISBN: 0306418436; http://www.amazon.com/exec/obidos/ASIN/0306418436/icongroupinterna

Books

309

•

Molecular Biology of Diabetes II: Insulin Action, Effects on Gene Expression and Regulation, and Glucose Transport by Boris Draznin, Derek Leroith (Editor) (1994); ISBN: 0896032876; http://www.amazon.com/exec/obidos/ASIN/0896032876/icongroupinterna

•

Molecular Mechanisms to Regulate the Activities of Insulin-Like Growth Factors: Proceedings of the 4th International Symposium on Insulin-Like Growth Factors, at Tokyo International Forum, Tokyo, Japan, 21-24 October 1997 (International Congress Series, No. 1151) by Ja International Symposium on Insulin-Like Growth Factors 1997 Tokyo, et al (1998); ISBN: 004448254X; http://www.amazon.com/exec/obidos/ASIN/004448254X/icongroupinterna

•

Muscle Morphology & the Insulin Resistance Syndrome: A Population-Based Study of 70 Year-Old Men in Uppsala (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1063) by Anu Hedman (2001); ISBN: 9155450830; http://www.amazon.com/exec/obidos/ASIN/9155450830/icongroupinterna

•

My Doctor Says I Have a Little Diabetes: Understanding & Controlling Type Ii, NonInsulin-Dependent Diabetes by Martha Hope McCool, Sandra Woodruff (1999); ISBN: 0895298600; http://www.amazon.com/exec/obidos/ASIN/0895298600/icongroupinterna

•

Natural Supplements for Diabetes: Reduce Your Risk and Lower Your Insulin Dependency With Natural Remedies by Frank Murray, Len Saputo (2003); ISBN: 1571743278; http://www.amazon.com/exec/obidos/ASIN/1571743278/icongroupinterna

•

Non-insulin-dependent Diabetes (Bailliere's Clinical Endocrinology and Metabolism) by Nattrass, Hull; ISBN: 0702012947; http://www.amazon.com/exec/obidos/ASIN/0702012947/icongroupinterna

•

Non-Insulin-Dependent Diabetes: Its Present and Future: Proceedings by P. H. Sonksen (Editor) (1984); ISBN: 0199220042; http://www.amazon.com/exec/obidos/ASIN/0199220042/icongroupinterna

•

Nutrient Regulation of Insulin Secretion (Portland Press Research Monograph, 1) by Peter R. Flatt (Editor) (1992); ISBN: 1855780046; http://www.amazon.com/exec/obidos/ASIN/1855780046/icongroupinterna

•

Oncogenes and Human Cancer Blood Groups in Cancer Copper and Inflammation Human Insulin (Progress in Clinical Biochemistry and Medicine, Vol 2) by T. L. J. Boehm (1985); ISBN: 0387155678; http://www.amazon.com/exec/obidos/ASIN/0387155678/icongroupinterna

•

Pathogenesis of Non-Insulin Dependent Diabetes Mellitus (1989); ISBN: 083167444X; http://www.amazon.com/exec/obidos/ASIN/083167444X/icongroupinterna

•

Pathogenesis of Non-Insulin Dependent Diabetes Mellitus (Karolinska Institute Nobel Conference Series) by Valdemar Grill, Suad Efendic (Editor) (1989); ISBN: 0881674443; http://www.amazon.com/exec/obidos/ASIN/0881674443/icongroupinterna

•

Physicians Guide to Insulin-Dependent (038); ISBN: 0945448015; http://www.amazon.com/exec/obidos/ASIN/0945448015/icongroupinterna

•

Physicians Guide to Non Insulin Dependent (Type II Diabetes) by Amer. Diabetes Assn. (1988); ISBN: 0945448007; http://www.amazon.com/exec/obidos/ASIN/0945448007/icongroupinterna

310 Insulin

•

Plasminogen Activator Inhibitor-1 & the Insulin Resistance Syndrome (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1150) by Liisa Byberg (2002); ISBN: 9155453074; http://www.amazon.com/exec/obidos/ASIN/9155453074/icongroupinterna

•

Protein Kinase C in Insulin Action, Resistance and Secretion (Medical Intelligence Unit) by Robert V. Farese (1994); ISBN: 1570592187; http://www.amazon.com/exec/obidos/ASIN/1570592187/icongroupinterna

•

Psychological & Medical Well-Being & Their Relation in Adults With InsulinDependent Diabetes Mellitus (Studia Psychologica Et Pedagogica Series Altera , No 127) by Bjorn Karlson (1997); ISBN: 9122017461; http://www.amazon.com/exec/obidos/ASIN/9122017461/icongroupinterna

•

Psychological Factors & Metabolic Control in Insulin-Dependent Diabetes Mellitus by Ulf Stenstrom (1997); ISBN: 9122017399; http://www.amazon.com/exec/obidos/ASIN/9122017399/icongroupinterna

•

Pumping Insulin: Everything You Need for Success With an Insulin Pump by Ruth Roberts M.A., et al (2000); ISBN: 1884804845; http://www.amazon.com/exec/obidos/ASIN/1884804845/icongroupinterna

•

Science and Civilisation in China: Volume 5, Chemistry and Chemical Technology, Part 3, Spagyrical Discovery and Invention: Historical Survey from Cinnabar Elixirs to Synthetic Insulin by Joseph Needham (Author), C. Cullen (Editor) (1976); ISBN: 0521210283; http://www.amazon.com/exec/obidos/ASIN/0521210283/icongroupinterna

•

Stability of Insulin: Studies on the Physical and Chemical Stability of Insulin in Pharmaceutical Formulation by Jens Brange (1994); ISBN: 0792388747; http://www.amazon.com/exec/obidos/ASIN/0792388747/icongroupinterna

•

Syndrome X : Managing Insulin Resistance by Deborah S. Romaine (Author), et al (2000); ISBN: 0380814447; http://www.amazon.com/exec/obidos/ASIN/0380814447/icongroupinterna

•

The Carbohydrate Addict's Healthy Heart Program: Break Your Carbo-Insulin Connection to Heart Disease by Richard F., Dr. Heller, et al; ISBN: 0345426118; http://www.amazon.com/exec/obidos/ASIN/0345426118/icongroupinterna

•

The Discovery of Insulin by Michael Bliss (1984); ISBN: 0226058980; http://www.amazon.com/exec/obidos/ASIN/0226058980/icongroupinterna

•

The Insulin-Like Growth Factors and Their Regulatory Proteins: Proceedings of the Third International Symposium on Insulin-Like Growth Factors, Sydn by P.D. Gluckman, et al; ISBN: 0444817565; http://www.amazon.com/exec/obidos/ASIN/0444817565/icongroupinterna

•

The Insulin-Like Growth Factors: Structure and Biological Functions (Oxford Medical Publications) by Paul N. Schofield (Editor), Paul N. Scholfield; ISBN: 0198542704; http://www.amazon.com/exec/obidos/ASIN/0198542704/icongroupinterna

•

The Other Diabetes: Your Guide to Living With Non-Insulin Dependent (Type II Diabetes) by Dorothea F. Sims (1988); ISBN: 0945448252; http://www.amazon.com/exec/obidos/ASIN/0945448252/icongroupinterna

•

The Role of Insulin-Like Growth Factors in the Nervous System (Annals of the New York Academy of Sciences, Vol 692) by Mohan K. Raizada, Derek Leroith (Editor)

Books

311

(1993); ISBN: 0897667891; http://www.amazon.com/exec/obidos/ASIN/0897667891/icongroupinterna •

The Sun, the Rain & the Insulin: Growing Up With Diabetes by Joan Maccracken, et al; ISBN: 0964601850; http://www.amazon.com/exec/obidos/ASIN/0964601850/icongroupinterna

•

The Type II Diabetes Diet Book: The Insulin Control Diet: Your Fat Can Make You Thin by Calvin Ezrin MD, et al; ISBN: 1565658078; http://www.amazon.com/exec/obidos/ASIN/1565658078/icongroupinterna

•

The World Market for Medicaments Containing Insulin in Dosage Form or Retail Packings: A 2004 Global Trade Perspective [DOWNLOAD: PDF]; ISBN: B000134BYM; http://www.amazon.com/exec/obidos/ASIN/B000134BYM/icongroupinterna

•

Think Like a Pancreas : A User's Guide to Managing Diabetes with Insulin by Gary Scheiner (Author) (2004); ISBN: 1569244367; http://www.amazon.com/exec/obidos/ASIN/1569244367/icongroupinterna

•

Treating Cancer with Insulin Potentiation Therapy by Ross A. Hauser, Marion A. Hauser (2002); ISBN: 0966101065; http://www.amazon.com/exec/obidos/ASIN/0966101065/icongroupinterna

•

Understanding Insulin Action (1989); ISBN: 074580473X; http://www.amazon.com/exec/obidos/ASIN/074580473X/icongroupinterna

•

Understanding Insulin Action: Principles and Molecular Mechanisms (Ellis Horwood Series in Biomedical Sciences) by J. Espinal (1989); ISBN: 999957193X; http://www.amazon.com/exec/obidos/ASIN/999957193X/icongroupinterna

•

Using Insulin, Everything You Need for Success With Insulin by John Walsh, et al (2003); ISBN: 1884804853; http://www.amazon.com/exec/obidos/ASIN/1884804853/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “insulin” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Absorption of injected insulin; a clinical-pharmacological study. [Translated from the Danish]. Author: Binder, Christian.; Year: 2003; Copenhagen, Munksgaard, 1969

•

Fiftieth Anniversary Insulin Symposium; proceedings of an international symposium sponsored by the Lilly Research Laboratories and held at the Lilly Center,

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

312 Insulin

Indianapolis, Indiana, October 18-20, 1971. Author: Lilly Research Laboratories.; Year: 1966; [New York, American Diabetes Assn., c1972] •

Great Scott; Ernest Lyman Scott's work with insulin in 1911. Author: Scott, Aleita Hopping.; Year: 1966; Bogota, N. J. Scott [c1972]

•

Impact of insulin on metabolic pathways; international symposium commemorating the 50th anniversary of insulin, 24 to 29 October 1971, Jerusalem, Israel, under the distinguished patronage of Charles H. Best. Edited by Eleazar Shafrir. Author: Shafrir, Eleazar.; Year: 1963; New York, Academic Press [c1972]; ISBN: 0126380503 http://www.amazon.com/exec/obidos/ASIN/0126380503/icongroupinterna

•

Insulin action, edited by Irving B. Fritz. Proceedings of a symposium. held at Toronto, Canada, October 25-27, 1971. Author: Fritz, Irving B.; Year: 1969; New York, Academic Press, 1972

•

Insulin and thyroid hormones in relation to mammary development in hypophysectomized rabbits. Author: Norgren, A. (Allan); Year: 1959; Lund, Gleerup, 1967

•

Insulin in serum; a review. Author: Gjedde, Flemming.; Year: 1962; Copenhagen, Costers Bogtrykkeri, 1969

•

Insulin, membranes, and metabolism. Author: Rieser, Peter.; Year: 1938; Baltimore, Williams; Wilkins, 1967

•

Mechanism and regulation of insulin secretion. [Edited by] R. Levine [and] E. F. Pfeiffer. Author: Levine, Rachmiel,; Year: 1967; [Milano, Casa editrice Il Ponte, 1968]

•

Normoglycemic glycosuria. The influence of glycosuria and hyperglycemia on glucose tolerance and insulin requirements in diabetes mellitus. Author: Smith, Kendrick Adelbert,; Year: 1964; Chicago, 1937

•

Regulation of the increased adrenomedullary secretion by drugs; effects of drugs on the urinary excretion of adrenaline and noradrenaline under insulin shock of rats. Author: Manninen, Kimmo.; Year: 2003; Turku, 1969

•

Specification for hypodermic syringes for insulin injection; Luer fitting. Author: British Standards Institution.; Year: 1964; London [1962]

•

The relationship of insulinogenic reserve to diabetic instability. Author: Cremer, Guillermo M.,; Year: 1999; [Minneapolis] 1969

Chapters on Insulin In order to find chapters that specifically relate to insulin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and insulin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “insulin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on insulin: •

Advanced Carbohydrate Counting: Using an Insulin Pump Source: in Warshaw, H.S. and Bolderman, K.M. Practical Carbohydrate Counting: A How-to-Teach Guide for Health Professionals. Alexandria, VA: American Diabetes Association. 2001. p. 37-41.

Books

313

Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $12.95 plus shipping and handling. ISBN: 1580401236. Summary: Advanced carbohydrate counting is appropriate for people who use multiple daily injections (MDI) of insulin or continuous subcutaneous insulin infusion (CSII) via an insulin pump. Their goal is to learn to match the amount of rapid (lispro or aspart) or short acting (regular) insulin they take with or before eating to the amount of carbohydrate they choose to eat. This chapter on advanced carbohydrate counting for patients using an insulin pump is from a handbook that helps health care providers teach patients with diabetes how to use carbohydrate counting as one part of their diabetes management plan. The author reviews the rationale for this management strategy and reminds readers that their patients must learn and use advanced carbohydrate counting for several weeks or months before beginning pump therapy. Specific topics covered include insulin regimens, basal rates, and bolus doses. The chapter concludes with representative case studies, including the situation, diabetes medications, food habits and daily schedule, and action plans for patients described in the studies. •

Adjustment of Insulin and Oral Agent Therapy Source: in Devlin, J.T. and Schneider, S.H., eds. Handbook of Exercise in Diabetes. Alexandria, VA: American Diabetes Association. 2002. p.365-376. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $69.95 plus shipping and handling. ISBN: 1580400191. Summary: Hypoglycemia (low blood glucose) in patients with insulin-treated diabetes may occur both during and after exercise. Rational strategies for its prevention are based on adjustments of insulin therapy. This chapter on the adjustment of insulin and oral agent therapy is from a book that provides a practical, comprehensive guide to diabetes and exercise for health care professionals involved in patient care. Specific insulin adjustments need to be individualized for a given patient based on his or her experience and the intensity and duration of exercise. To make adjustments in insulin dosage, the patient must have a sound knowledge of basic principles and must monitor his or her blood glucose frequently. Exercise-induced hypoglycemia usually cannot be avoided by changing the insulin injection site. Patients on intensive insulin therapy should, in general, be able to participate in sports without an excessively high risk of exerciseinduced hypoglycemia. During and after long term exercise, type 2 diabetic patients on sulfonylurea therapy may require a dose reduction of the insulin secretagogue and additional carbohydrate intake to prevent hypoglycemia. 3 tables. 21 references.

•

Genetics of Non-Insulin-Dependent (Type II) Diabetes Mellitus Source: in Coggins, C.H., Hancock, E.W., and Levitt, L.J., eds. Annual Review of Medicine: Selected Topics in the Clinical Sciences. Palo Alto, CA: Annual Reviews Inc. 1996. Volume 47: 509-531. Contact: Available from Annual Reviews Inc. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (800) 523-8635. Fax (415) 424-0910. PRICE: $52.00. ISBN: 0824305477. ISSN: 00664219. Individual article reprints available from Annual Reviews Preprints and Reprints. (800) 347-8007 or (415) 259-5017. Base price $13.50 per article.

314 Insulin

Summary: In this entry from the Annual Review of Medicine, the authors discuss the genetics of noninsulin-dependent diabetes mellitus (NIDDM). The authors note that the genetic component is heterogeneous and in some patients is probably complex, involving multiple genes. Specific genetic defects have been identified for rare monogenic forms of NIDDM: maturity-onset diabetes of the young (MODY), syndromes of extreme insulin resistance, and diabetes-deafness syndromes. In contrast, the genes involved in common forms of NIDDM are still uncertain. Mutations have been extensively searched in genes regulating insulin signaling and secretion. The authors conclude that new insights are expected in the near future from the systematic scanning of the genome for linkage with NIDDM. 5 figures. 157 references. (AA-M). •

Insulin Pump Therapy with Continuous Subcutaneous Insulin Infusion and Exercise in Patients with Type 1 Diabetes Source: in Devlin, J.T. and Schneider, S.H., eds. Handbook of Exercise in Diabetes. Alexandria, VA: American Diabetes Association. 2002. p.377-381. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $69.95 plus shipping and handling. ISBN: 1580400191. Summary: Insulin pump therapy with continuous subcutaneous insulin infusion is commonly used to implement intensive diabetes management in patients with type 1 diabetes. Insulin pump therapy provides great flexibility for adjusting both meal doses and basal insulin requirements for exercise. This chapter on insulin pump therapy and exercise is from a book that provides a practical, comprehensive guide to diabetes and exercise for health care professionals involved in patient care. For certain activities, patients can remove their pumps for short periods (less than 1 hour) without any consequences. Pump removal for a longer period requires subcutaneous administration of a bolus of insulin to cover the insulin pump disconnect time. Skill in using insulin pump therapy to modify the infusion rate for particular activities is achieved through frequent self-monitoring of blood glucose (SMBG) and patient experience. The authors briefly consider specific sports, including water sports, contact sports, and skiing, skating and winter sports. 5 references.

•

Insulin Pump Therapy and Carbohydrate Counting for Pump Therapy: Carbohydrate-to-Insulin Ratios Source: in Franz, M.J., et al, eds. Core Curriculum for Diabetes Education. 4th ed.: (Volume 2) Diabetes Management Therapies. Chicago, IL: American Association of Diabetes Educators (AADE). 2001. p. 201-228. Contact: Available from American Association of Diabetes Educators. AADE Member Service Center, 100 W. Monroe Street, Suite 400, Chicago, IL 60603. (800) 338-3633. Fax (312) 424-2427. Website: www.diabeteseducator.org. PRICE: Individual volume $45.00 for members and $60.00 for nonmembers; complete 4-volume set $149.95 for members and $199.95 for nonmembers; plus shipping and handling. ISBN: 1881876063 (Volume 2); 1881876098 (4-volume set). Summary: Insulin therapy should be integrated into the usual eating and exercise habits of the person with diabetes. Insulin pump therapy provides an excellent means of achieving this goal. Carbohydrate counting involving carbohydrate-to-insulin ratios is used to implement medical nutrition therapy (MNT) for insulin pump therapy. This chapter on insulin pump therapy and carbohydrate counting is from a book in a series

Books

315

of four texts that make up a Core Curriculum, designed primarily to help educators prepare for the Certified Diabetes Educator (CDE) exam. Topics include the indications for patient use of insulin pump therapy, the limitations of insulin pump therapy, selection criteria for pump candidates, insulin pumps that are currently available in the United States, how to fine-tune pump therapy, how to evaluate a patient's understanding of and ability to use carbohydrate counting, and the use of carbohydrate counting for pattern management. The chapter lists the learning objectives for that chapter, presents information in outline and bulleted format, summarizes the key educational considerations, offers self review questions and questions for discussion, presents six practice case reports, and concludes with a list of references. A post-test and the answers to the post-test questions are appended to the chapter. 2 figures. 54 references. •

Insulin Use in the Elderly Source: in Cooper, J.W. Diabetes Mellitus in the Elderly. Binghamton, NY: Pharmaceutical Products Press. 1999. p. 61-81. Contact: Available from Pharmaceutical Products Press. 10 Alice Stret, Binghamton, NY 13904-1580. (800)429-6784. E-mail: [email protected]. Website: www.haworthpressinc.com. PRICE: $49.95 plus shipping and handling. ISBN: 0789006820. Summary: Recent evidence has shown that near euglycemic (optimal levels of blood glucose, or sugar) control can reduce macrovascular and microvascular complications in individuals with type 1 and type 2 diabetes mellitus. Large numbers of elderly type 2 diabetes patients progress to insulin therapy after oral agent failure. This article on insulin use in the elderly patient is from a volume that is devoted to the diagnosis and treatment of diabetes mellitus in the elderly. The authors outline treatment goals and age related considerations for insulin use in the elderly with type 1 and type 2 diabetes. Good glycemic control is a goal of diabetes therapy in the elderly; unfortunately, incidence of severe hypoglycemia (low levels of glucose in the blood) increases with tighter control. Reduced counterregulatory responses and awareness to hypoglycemia (the patient does not recognize the symptoms) and advanced atherosclerosis place the elderly at increased risk for morbidity (complications or associated illnesses) and mortality (death) from hypoglycemia. Physicians must consider altered drug utilization and use of multiple medications in the geriatric population. Comorbidities, functional impairment, nutritional issues, and age related learning characteristics present therapeutic challenges. The authors describe the pharmacodynamics and physiologic effects of available insulin preparations and their application for clinical use in the elderly. Advantages and disadvantages of various regimens used in the elderly with type 1 and type 2 diabetes are discussed. 3 tables. 68 references.

•

Metabolic Basis of Insulin Secretion Source: in Sperling, M.A. Type I Diabetes: Etiology and Treatment. Totowa, NJ: Humana Press Inc. 2003. p. 115-144. Contact: Available from Humana Press Inc. 999 Riverview Drive, Suite 208, Totowa, NJ 07512. (973) 256-1699. Fax (973) 256-8341. E-mail: [email protected]. Website: www.humanapress.com. PRICE: $165.00; plus shipping and handling. ISBN: 896039315. Summary: The increasing incidence of diabetes worldwide has prompted a rapid growth in the pace of scientific discovery and clinical understanding of this disease. This chapter on the metabolic basis of insulin secretion is from a book in which well-

316 Insulin

recognized physicians and researchers review the latest thinking about the causes of type 1 diabetes and the best approaches to treating both its acute and chronic complications. The authors discuss general principles of nutrient sensing, a basic model of the glucose sensing system, fatty acids as insulin secretagogues, amino acids as insulin secretagogues, mitochondria as metabolic signal generators of fuel-stimulated beta cells, and neural and endocrine regulation of insulin release. The authors conclude with a brief discussion of the vigorous attempts that are being made to develop pharmacological agents that might modify critical metabolic pathways of beta cells and thus influence insulin secretion. Molecular bioengineering approaches take advantage of the wealth of fundamental knowledge about substrate-controlled insulin release in attempts to develop implantable cell-based devices that may aid or replace impaired beta cells in diabetes. 7 figures. 115 references. •

Solving Insulin Delivery Problems Source: in Touchette, N. Diabetes Problem Solver. Alexandria, VA: American Diabetes Association. 1999. p. 123-148. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $19.95 for members; plus shipping and handling. ISBN: 1570400091. Summary: This chapter deals with solving insulin delivery problems in people who have diabetes. In people who have type 1 diabetes, the body does not make the insulin it needs, so insulin must be injected. In people who have type 2 diabetes, the body does not make enough insulin or it may not respond to insulin the way it should; therefore, extra insulin may be needed to keep diabetes under control. Most of the problems with insulin involve its delivery. Several types of problems occur at injection sites, including a loss of fat at the injection site or an overgrowth of fat cells at the injection site. People may also experience burning, itching, or a rash at the injection site. Although insulin allergy is becoming less common, some people may still experience an allergic response to an insulin preparation. Another problem is use of inactive insulin, which could cause a person to lose control of his or her blood glucose level. People who switch to human insulin from animal insulin may experience hypoglycemia or hyperglycemia. Other problems with insulin delivery involve timing insulin injections so that they most closely mimic what the body does naturally, adjusting to an insulin pump, and coping with the side effects of intensive therapy. The chapter discusses most of these problems in terms of their symptoms; who is at risk for the problem; and how the problem should be handled, treated, and prevented. In addition, the chapter provides information on pancreas transplants. 6 figures. 1 table.

•

Role of Short-Acting Insulin Analogues in Sport Source: in Burr, B. and Nagi, D., eds. Exercise and Sport in Diabetes. Somerset, NJ: John Wiley and Sons. 1999. p. 97-108. Contact: Available from John Wiley and Sons. One Wiley Drive, Somerset, NJ 08875. (800) 225-5945 or (732) 469-4400. Fax (732) 302-2300. E-mail: [email protected]. Website: www.wiley.com. PRICE: $74.95 plus shipping and handling. ISBN: 0471984965. Summary: This chapter examines the role of a new short-acting insulin analog, known as insulin lispro or Humalog, and its use in the treatment of exercising patients who have diabetes. The analog, which has been synthesized by switching the order of lysine and proline at positions B28 and B29 in the insulin B chain, has a lesser tendency for self

Books

317

association than human soluble insulin. Various factors determine the metabolic and hormonal response to exercise in people who have type 1 diabetes, including the intensity and duration of exercise, the level of metabolic control, the type and dose of insulin injected before the exercise, the site of the insulin injection, and the timing of the previous insulin injection and meal relative to the exercise. Hyperinsulinemia is the underlying cause for the excessive fall in blood glucose during exercise. Clinical trials of insulin lispro show that, compared with human soluble insulin, it decreases the postprandial rise in blood glucose, reduces both moderate and severe hypoglycemia, improves long term control, and satisfies patients. A study comparing the blood glucose response to exercise in people who have type 1 diabetes using either human soluble insulin or insulin lispro shows that hyperinsulinemia was greater during early exercise and tended to be lower during late exercise. Thus, the much faster absorption of the insulin analog can either augment or reduce the fall in plasma glucose during exercise, depending on the interval between insulin injection and the time of exercise. 7 figures. 2 tables. 15 references. •

How To Get the Most Out of Your Insulin Therapy Source: in Carlisle, B.A.; Kroon, L.A.; Koda-Kimble, M.A. 101 Medication Tips for People with Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 58-61. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This chapter explains how people who have diabetes can get the most out of insulin therapy. Although the abdomen, arms, thighs, and hips are common sites for injections, many health care practitioners recommend using the abdomen as the primary site because it is a large, easily reached area and insulin enters the bloodstream quickly. In addition, it is the site least affected by exercise. Rotating sites will help avoid the development of lumps. Syringes may be prepared in advance if a good, clean technique is used and the storage containers are labeled with the date of preparation. Mixing regular and lente insulin may slow and prolong the action of regular insulin if the mixture is not used within 15 minutes. Switching from lente to NPH insulin will avoid this problem. Insulin can be stored at room temperature for 1 month if the vial is kept in a place where it will not be exposed to temperature extremes.

•

Common Side Effects of Insulin Source: in Carlisle, B.A.; Kroon, L.A.; Koda-Kimble, M.A. 101 Medication Tips for People with Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 62-65. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This chapter identifies the common side effects of insulin, including weight gain, hypoglycemia, and lumps at the injection site. Although most people who use insulin will gain weight, it can be minimized by properly adjusting the dose to just the right amount a person needs to keep blood glucose levels within the target range without causing too many lows. People who experience night sweats and morning headaches may be injecting too much insulin in relation to their evening meal or too much of the wrong type of insulin. Testing blood glucose at 3:00 a.m. and again first

318 Insulin

thing in the morning for several days may help determine whether a change needs to be made to the insulin regimen. Lumps and fat pads, which are not dangerous, occur when insulin is repeatedly injected into the same place. If injection sites are carefully rotated, a person should not have to use the same site more than once every 2 weeks. •

Adjusting Your Insulin to Avoid Hypoglycemia Source: in Lincoln, T.A.; Eaddy, J.A. Beating the Blood Sugar Blues. Alexandria, VA: American Diabetes Association. 2001. p.44-54. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $12.95 plus shipping and handling. ISBN: 1580400485. Summary: This chapter is from a book that offers first hand knowledge from two doctors who have more than 100 years of combined experienced with the day-to-day balancing act of blood glucose (sugar) and diabetes. The authors, both of whom have type 1 diabetes, share their own stories as well as those of over 40 of their patients. In this chapter, the authors offer advice about how to adjust insulin dosages to better control blood glucose levels. The authors remind readers that before they make any changes to their treatment plan to discuss their ideas and what they want to change with both the doctor and the diabetes educator. When one adjusts the insulin dose, the other factors that affect the blood sugar should be kept as steady as possible. This means that patients need to manage their meal plan, exercise, and stress to prevent major changes in them at the same time that the insulin dose is being adjusted. The authors describe the different types of insulin and the usual time of action of each one. The authors also review factors that affect insulin absorption, including local heat, environmental temperature, exercise, the site of injection, the depth of injection, the type of insulin, and the insulin mixture. Illness can also affect insulin action and blood sugar control. The chapter concludes with a discussion of how to choose an insulin plan. 3 figures. 3 tables.

•

Insulin Therapy Source: in Edelman, S.V. and Henry, R.R. Diagnosis and Management of Type 2 Diabetes. Caddo, OK: Professional Communications, Inc. 2002. p. 121-148. Contact: Available from Professional Communications, Inc., Fulfillment Center, PO Box 10, Caddo, OK 74729-0010. (800)337-9838. Fax (580)367-9989. E-mail: [email protected]. ISBN: 1884735754. PRICE: $21.95, plus shipping and handling. Summary: This chapter on the use of insulin therapy is from a handbook for primary care providers that offers a concise overview of the diagnosis and management of type 2 diabetes. Insulin therapy most commonly is reserved for patients who have failed an adequate trial of diet, exercise, and oral antidiabetes agents. However, institution of insulin therapy is commonly delayed inappropriately in patients failing oral antidiabetes agents. The authors encourage early use of insulin soon after it is evident that oral antidiabetes agents are failing. The authors focus on the different insulin regimens commonly used to normalize glucose levels and glycosylated hemoglobin (HbA1c, a measure of blood glucose levels over time) in patients with type 2 diabetes mellitus. Topics include selecting an insulin preparation, the application of intensive insulin therapy, combination therapy, multiple injection regimens, insulin pump therapy, alternative insulin delivery systems, complications of insulin therapy, and the use of islet cell transplantation. 2 figures. 5 tables. 5 references.

Books

•

319

Ins and Outs of Insulin Source: in American Diabetes Association. American Diabetes Association Complete Guide to Diabetes: The Ultimate Home Diabetes Reference. 2nd ed. Alexandria, VA: American Diabetes Association. 1999. p. 93-133. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $23.95 plus shipping and handling. ISBN: 1580400388. Summary: This chapter provides an overview of insulin, which is a hormone that helps cells use glucose. The chapter begins by describing the pharmacokinetics of various types of insulin, including regular insulin, lispro insulin, NPH, lente, and ultralente. Mixtures of insulins may also be used. The chapter then explains how to buy and store insulin. This is followed by guidelines for administering insulin, including injecting insulin using syringes and injection devices such as injection aids, infusers, jet injectors, pen injectors, and aids for the visually impaired; rotating injection sites; and purchasing and choosing an insulin pump. In addition, the chapter describes insulin plans for people who have type 1 diabetes, type 2 diabetes, and gestational diabetes. Plans include one shot a day, more than one shot per day, and intensive insulin therapy. 9 figures.

•

General Information About the Use of Insulin in Type 2 Diabetes Source: in Carlisle, B.A.; Kroon, L.A.; Koda-Kimble, M.A. 101 Medication Tips for People with Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 40-57. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This chapter provides general information on the use of insulin in type 2 diabetes. Over time, people who are taking oral agents may need to take insulin, either temporarily or permanently, depending on their glucose level and other medical conditions. Insulin, either alone or in combination with oral medications, may be needed by people who respond poorly to a combination of oral medications. Some people may delay insulin therapy by more rigorous attention to diet and exercise, or perhaps by adding another oral medication. Injecting NPH insulin in the morning and before dinner helps people avoid very high and very low insulin levels. Regular lispro insulin may be used to improve a person's blood glucose control because they get into the body more quickly and have a shorter duration of action. Lispro, which is taken within 15 minutes before a meal, may be more convenient than regular insulin for people who are very busy or have unpredictable meal schedules. Although premixed insulins can help some people simplify therapy, they offer very little flexibility in meal planning because the dose of the short acting insulin is strongly determined by the amount of carbohydrate in each meal. Insulin requirements vary by person. More frequent injections provide the opportunity to achieve better glucose control with lower total daily doses of insulin. People who inject high doses of insulin but continue to have uncontrolled diabetes may need to test their blood glucose levels more frequently to see whether the type of insulin and the number of injections are optimal. The addition of an oral medication to insulin injections may also improve blood glucose control and decrease insulin requirements. Troglitazone is one medication that can be added to an insulin regimen. People who had been treated with insulin before the development of the newest oral medications may be

320 Insulin

able to switch to a combination of oral medications. With a few exceptions, switching to a different brand of insulin is safe. Insulin doses should be adjusted before beginning a vigorous exercise program. In the future, there may be ways other than injection to administer insulin. •

Diabetes and Insulin Action Source: in Kuh, D.; Ben-Shlomo, Y. A Life Course Approach to Chronic Disease Epidemiology. Cary, NY: Oxford University Press. 1997. p. 78-100. Contact: Available from Oxford University Press. 2001 Evans Road, Cary, NY 27513. (800) 451-7556. PRICE: $65.00. ISBN: 0192627821. Summary: This chapter reviews the evidence that the risk of type 2 diabetes in adult life may be established by nutrition and growth in fetal life. Five studies have examined the relation of size at birth to impaired glucose tolerance or type 2 diabetes in later life. Two studies in England found a strong inverse association between birthweight and the prevalence of glucose intolerance in later life. The association of reduced size at birth with type 2 diabetes has also been confirmed in three other populations; however, the relationship was less strong than in the original English populations and the form of the relationship was nonlinear. Other studies in children and young adults show that plasma glucose levels after oral glucose challenge are inversely related to birthweight. Recent studies suggest that glucose intolerance is related more strongly to thinness at birth, measured by low ponderal index, than to low birthweight. Suggestions that the association can be accounted for by selective survival of low birthweight infants genetically predisposed to diabetes are not compatible with historical data on infant mortality rates. The association between size at birth and diabetes could be mediated through impairment of insulin secretion, resistance to the action of insulin in lowering blood glucose levels, or both. The association of thinness at birth with insulin resistance and glucose intolerance in adult life could also have a genetic or an environmental explanation. The article highlights research on these mediating influences. It concludes that, whatever the mechanism of the association between thinness at birth and risk of type 2 diabetes later in life, control of obesity is likely to be effective in reducing the risk of diabetes in individuals who were thin at birth. 3 figures. 3 tables. 72 references. (AAM).

•

For People with Type 1 (Insulin-Dependent) Diabetes Source: in Biermann, J. and Toohey, B. Diabetic's Book: All Your Questions Answered. 4th ed. New York, NY: Jeremy P. Tarcher-Putnam. 1998. p. 124-150. Contact: Available from Jeremy P. Tarcher-Putnam. 200 Madison Avenue, New York, NY 10016. (800) 788-6262 or (212) 951-8891. Fax (201) 896-8569. PRICE: $13.95 plus shipping and handling. ISBN: 0874779243. Summary: This chapter uses a question and answer format to provide people who have type 1 diabetes with information on using insulin to manage this disease. The chapter explains that insulin is a hormone that helps cells take up sugar from the blood and that people who have type 1 diabetes must use insulin to replace their body's lack of the hormone. Topics include determining where, how, and when to inject it; overcoming a fear of needles; using injection aids and the insulin infusion pump; taking insulin during an illness; storing and traveling with bottles of insulin; handling injections when eating at a restaurant; adjusting insulin administration when traveling; managing low blood sugar or an insulin reaction; and exercising alone. 1 figure. 1 table.

Books

•

321

Insulin Resistance and Hypertension Source: in Schrier, R.W. and Wilcox, C.S., eds. Atlas of Diseases of the Kidney. Volume 3: Hypertension and the Kidney. Philadelphia, PA: Current Medicine, Inc. 1999. p. 5.1-5.10. Contact: Available from Blackwell Science, Inc. 350 Main Street, Malden, MA 02148. (800) 215-1000 or (781) 388-8250. Fax (781) 388-8270. E-mail: [email protected]. PRICE: $75.00 plus shipping and handling. ISBN: 063204389X. Summary: This chapter uses a series of figures to discuss insulin resistance and hypertension. Insulin resistance is associated with increased risk of cardiovascular disease, and it may be the link between hypertension and dyslipidemia. Data show that approximately 25 percent to 40 percent of nonobese, nondiabetic patients who have hypertension are insulin resistant. Researchers have also observed insulin resistance in genetic and acquired animal models of hypertension. A syndrome, termed syndrome X, includes a constellation of insulin resistance, decreased high density lipoprotein cholesterol, and hypertension. Although various causes have been proposed, it is unclear whether insulin resistance or reactive hyperinsulinemia, or both, actually cause hypertension. Recent findings that insulin sensitizing agents attenuate the development of hypertension provide support for this hypothesis. However, these agents may lower blood pressure by different mechanisms. Type 2 diabetes represents an extreme of insulin resistance. The prevalence of hypertension increases twofold to threefold among people who have diabetes. Hypertension is associated with a fourfold increase in mortality among patients who have type 2 diabetes, and antihypertensive drug therapy has a beneficial effect on both macrovascular and microvascular disease. Although there is some concern that diuretics may augment insulin resistance, people who have diabetes benefit from antihypertensive therapy with diuretics. Different antihypertensive drugs have different renal protective effects. Angiotensin converting enzyme inhibitors decrease proteinuria and retard the progression of renal insufficiency in people who have diabetes but normal blood pressure and hypertension. Findings from studies evaluating the effects of calcium antagonists on the progression of diabetic nephropathy are varied. Additional studies are needed to evaluate the antihypertensive potential of insulin sensitizing agents in people who have type 2 diabetes. 31 figures. 19 references.

•

Nitty-Gritty 1: Insulin Treatment Source: in Siminerio, L.M. and Betschart, J. American Diabetes Association Guide to Raising a Child with Diabetes. 2nd ed. Alexandria, VA: American Diabetes Association. 2000. p. 17-42. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $16.95 plus shipping and handling. ISBN: 1580400272. Summary: This chapter, part of a book on raising a child with diabetes, discusses the use of insulin to manage diabetes. The chapter begins by describing the types of insulin available, including rapid acting (Humalog or lispro) insulin, short acting (regular) insulin, intermediate acting (NPH or lente) insulin, and long acting (ultralente) insulin. This is followed by an explanation of insulin dosages, the number of injections needed per day, and the steps involved in drawing up and administering insulin. Other topics include site rotation, insulin delivery devices such as insulin pens and insulin pumps, needle disposal, insulin adjustment based on food consumption and physical activity, and self injection. 16 figures. 2 tables.

322 Insulin

•

Insulin and Your Travels Source: in Kruger, D.F. Diabetes Travel Guide. Alexandria, VA: American Diabetes Association. 2000. p. 39-74. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400418. Summary: This chapter, part of a diabetes travel guide, provides detailed guidelines for packing and using insulin and insulin supplies such as syringes, a blood glucose meter, test strips, ketone strips, and a glucagon kit. The chapter advises readers to pack their insulin, syringes, blood glucose meter, test strips, ketone strips, and glucagon kit in their carry on bag; pack twice as much as they think they will need; have snacks or glucose products with them at all times; and carry a prescription or letter from their health care provider with information about the insulin and syringes they need. Other topics include caring for insulin in warm or cold climates, disposing of insulin supplies safely, creating a diabetes survival kit, obtaining insulin and syringes in foreign countries, and adjusting insulin and an insulin pump for various time zone changes. 5 appendices. 3 tables.

•

Intensive Insulin Therapy Source: in Michigan Diabetes Research and Training Center; Funnell, M.M., et al. Life with Diabetes: A Series of Teaching Outlines by the Michigan Diabetes Research and Training Center. 2nd ed. Alexandria, VA: American Diabetes Association. 2000. p. 591620. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $75.00 plus shipping and handling. ISBN: 1580400566. Summary: This teaching outline, part of a series of teaching outlines on living with diabetes, provides information about intensive insulin therapy. The outline includes a statement of purpose; prerequisites that participants should know before attending a particular session; objectives; materials needed for teaching a session; a recommended teaching method; a content outline that includes the general concepts to be covered, specific details, and instructor's notes or teaching tips; an evaluation and documentation plan; and suggested readings. Concepts covered in the outline include the objectives of intensive insulin therapy, the reasons for choosing intensive insulin therapy, the components of intensive insulin therapy, the advantages and disadvantages of intensive insulin therapy, and the resources needed to implement intensive insulin therapy. Other topics include insulin programs; the role of food and exercise in intensive insulin therapy; and the importance of blood glucose monitoring, insulin adjustments, close contact with a health care team, and continuing education in intensive insulin therapy. Visuals and handouts are also provided.

•

Regional Body Fat Distribution, the Insulin Resistance-Dyslipidemic Syndrome, and the Risk of Type 2 Diabetes and Coronary Heart Disease Source: in Devlin, J.T. and Schneider, S.H., eds. Handbook of Exercise in Diabetes. Alexandria, VA: American Diabetes Association. 2002. p. 197-234.

Books

323

Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $69.95 plus shipping and handling. ISBN: 1580400191. Summary: Visceral adipose tissue accumulation is an important factor to consider in the evaluation of health risks associated with obesity. This chapter is from a book that provides a practical, comprehensive guide to diabetes and exercise for health care professionals involved in patient care. In this chapter, the authors consider regional body fat distribution, the insulin resistance-dyslipidemic syndrome, and the risk of type 2 diabetes and coronary heart disease. The simultaneous presence of hyperinsulinemia, hyperapolipoprotein B, and small, dense LDL particles is associated with a 20 fold increase in the risk of ischemic heart disease. A simple and inexpensive screening test to identify a high risk form of abdominal obesity is to determine if the patient has the following: a waist circumference greater than 90 centimeters and triglyceride levels greater than 2.0 mmol per liter. Improvements in the metabolic risk profile resulting from endurance exercise training are more related to the volume of exercise than to its intensity. The authors conclude that from a public health standpoint, the greatest benefit would be to transform the largely sedentary population into moderately active individuals. Physicians and health professionals should keep in mind that the changes in lifestyle associated with the best compliance are those that are likely to have the greatest long term impact on cardiovascular health. 8 figures. 3 tables. 148 references. •

Effects of Insulin on the Vascular System Source: in Johnstone, M.T. and Veves, A. Diabetes and Cardiovascular Disease. Totowa, NJ: The Humana Press, Inc. 2001. p. 23-43. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $125.00, plus shipping and handling. ISBN: 089603755X. Summary: With over ten million diagnosed patients and another five million undiagnosed, diabetes mellitus and its complications is a major public health problem that will assume epidemic proportions as the population grows older. This chapter on the effects of insulin on the vascular system is from a textbook that offers physicians practical knowledge about cardiovascular disease and diabetes. This chapter is in Part I, which focuses on pathophysiology, including the mechanisms and risk factors for diabetic cardiovascular disease. The author first explains the general function of the vascular system, which is to allow the delivery of blood (which includes oxygen and nutrients) to the tissues according to their unique metabolic needs. After a brief discussion of the technical problems in research on the vascular system, the author then covers physiology of the system and pathophysiology of the metabolic syndrome (diabetes, hypertension or high blood pressure, and dyslipidemia, or disordered levels of fats in the blood). The author stresses that over the last 10 years it has become established that insulin is a vascular hormone. The vascular actions of insulin extend beyond its ability to increase skeletal muscle blood flow and glucose (sugar) uptake. Current data suggest that insulin modulates vascular tone, as well as vascular smooth muscle cell proliferation and migration via the release of nitric oxide and other yet unidentified mechanisms. Thus, the effects of insulin on the vascular system may be important in prevention or delay of cardiovascular disease progression. The altered state of the vascular system in the metabolic syndrome may contribute to the higher rates of hypertension and macrovascular (large blood vessel) disease. 6 figures. 83 references.

324 Insulin

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to insulin have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •

American Diabetes Association 1999 Resource Guide Source: Diabetes Forecast. 1999 Resource Guide: 1-104. January 1999. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This guide provides complete and up-to-date information on managing diabetes and begins with an article on ways that people can better manage their diabetes to prevent complications. This is followed by an extensive product listing designed to help readers identify diabetes products that are right for them. Products include new devices for home monitoring of blood glucose, aids for people who are visually impaired, new lancets and lancing devices, new insulin administration products, new prescription drugs for diabetes-related conditions, and miscellaneous products. In addition, the guide offers a complete analysis of all drugs available to treat type 2 diabetes and a description of how each drug works, a listing of diabetes education programs recognized for their quality and excellence by the American Diabetes Association, a listing of recognized health care providers, and a one-page guide to the programs and services available through the American Diabetes Association.

12

You will need to limit your search to “Directory” and “insulin” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “insulin” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

325

CHAPTER 8. MULTIMEDIA ON INSULIN Overview In this chapter, we show you how to keep current on multimedia sources of information on insulin. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on insulin is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “insulin” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “insulin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on insulin: •

Insulin Pump Therapy Source: New York, NY: American Journal of Nursing. 1994. Contact: Available from AJN Company. Multi-Media Products Division, 555 West 57th Street, New York, NY 10019-2961. (800) CALL-AJN. Fax (212) 586-5462. PRICE: $250. Rental $95. Code no. 4389. Summary: This nursing education video program describes insulin infusion pump therapy, a diabetes treatment option that facilitates improved blood glucose control and allows for lifestyle flexibility. The program covers nursing implications, including management of insulin pump therapy, complications, education of the patient, insulin adjustment, programming the pump, and other techniques of use in the hospital or home setting. Complications, including infection and hypoglycemia, are also reviewed. (AA-M).

326 Insulin

•

Understanding Insulin Source: Timonium, MD: Milner-Fenwick, Inc. 1994. Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093. (800) 432-8433. Fax (410) 252-6316. PRICE: $175 (as of 1995); discounts available for AADE members. Order Number DB-25. Summary: This patient education videotape explains why injections of insulin may be needed to help control diabetes. The video covers the different types of insulin, including sources, action times, and concentration. Other topics include hypoglycemia; urine testing; dealing with sick days; and management guidelines. The program also introduces pattern management as a method of insuring that all elements of the diabetes care plan work together. The program is available in English or Spanish, and with closed captioning. (AA-M).

•

How to Measure and Inject Insulin Source: Minneapolis, MN: International Diabetes Center. 1992. (videocassette; cassette, slides). Contact: Available from International Diabetes Center. 5000 West 39th Street, Minneapolis, MN 55416. (612) 927-3393. PRICE: $95 Video, $10 Cassette, $75 Slides plus shipping and handling. Order number 004125 (videotape), 004126 (slides), 004127 (cassette). Summary: This program reviews the steps for measuring and injecting insulin. Designed for people newly diagnosed with diabetes or those who have recently been prescribed insulin, the videotape addresses patient concerns about self-injection. Topics include the basics on insulin and injections, the types of insulin, the best way to give injections, storage hints, syringes, avoiding infection, preparing insulin and syringes, injection sites, record-keeping, and syringe disposal. The program illustrates proper injection technique with step-by-step instruction on how to draw up, measure, and inject insulin.

•

Management of Insulin-Dependent Diabetes Source: Camp Hill, PA: Chek-Med Systems, Inc. 1993. Contact: Available from Chek-Med Systems, Inc. 200 Grandview Avenue, Camp Hill, PA 17011. (800) 451-5797. Fax (717) 761-0216. PRICE: $89 (as of 1995); bulk prices available. Item Number CV-23. Summary: This videotape for patients describes the three elements that comprise management of insulin-dependent diabetes mellitus (IDDM). The tape describes the importance of diet, exercise, and insulin administration, individually and collectively. The program stresses that proper management of these three elements help people with diabetes lead active, healthy, and productive lives. The program depicts real patients and real medical situations and is one of a 10-part series on diabetes. (AA-M).

•

Controlling My Diabetes: Step-By-Step Guide for Glucose Monitoring/Insulin Injection Source: Evanston, IL: Altschul Group Corporation. 1994.

Multimedia 327

Contact: Available from Altschul Group Corporation. 1560 Sherman Avenue, Suite 100, Evanston, IL 60201. (800) 421-2363 or (708) 328-6700. Fax (708) 328-6706. PRICE: $295 (as of 1995). Order no. 7842. Summary: This videotape program is one of a series of six videotapes that present a common sense approach for living with and controlling diabetes mellitus. This program presents two essential elements of health care for the person with diabetes: blood glucose monitoring and insulin injections. The program shows demonstrations with diabetes educators that illustrate proper procedures for both of these activities. Plus, instruction is provided on various types of insulin and the onset, peak, and duration of each. (AA-M). •

What is Diabetes? (Non-Insulin Dependent) Source: Timonium, MD: Milner-Fenwick, Inc. 1996. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093. (800) 432-8433 or (410) 252-1700. Fax (410) 252-6316. PRICE: List price $175; discounts available. Item number DB-33. Summary: This videotape, one of a series of patient education videos, provides an overview of noninsulin-dependent diabetes mellitus (NIDDM, or Type 2). The program delivers a concise picture of how diabetes affects the way blood sugar and insulin work, and summarizes diabetes treatment and self-care skills. The program summarizes symptoms, reviews healthy eating, exercise, medication, foot care, eye care, and the association between diabetes and heart disease. The program features a variety of patients and uses both live action and bold graphics to present the concepts. The video series is designed to provide an educational foundation on which patients and diabetes educators can build a practical program of diabetes management. The video reflects current American Association of Diabetes Educators (AADE) guidelines and is coproduced by the association. The video is available in English, Spanish, and closedcaptioned versions. (AA-M).

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “insulin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on insulin: •

Changing Nature of Diabetes Therapy: Insulin Therapy Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. (audiotape). Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Order number 000-87B. Summary: This audiotape is from a series of accredited continuing education audio programs and corresponding monographs designed to help the primary care physician manage patients with diabetes more effectively. In this program, moderator Steven Fox and guests discuss the evolution of insulin therapy, and the way they see the latest

328 Insulin

scientific and medical advances fitting into the day-to-day management of patients. Topics covered include the basic principles of recombinant technology; the relative immunogenicity of various insulin types; the theories that explain antibody production; the timing profiles of various insulin formulations; absorption rate variability; the principles of initiating insulin therapy and various regimens thereof; the advantages and disadvantages of intensive insulin therapy; and present research efforts regarding the investigation of hyperinsulinemia. The study guide includes a post-test quiz for earning Continuing Medical Education (CME) credit. 12 references. (AA-M). •

Therapeutic Dilemmas In Type II Diabetes Mellitus: Premixed Human Insulin Regimens Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. (audiotape). Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Order number 000-11A. Summary: This audiotape is the first in a series of three accredited continuing education audio programs and monographs that explore controversial issues of interest to the primary care physician who treats patients with diabetes. Dr. Alan O. Marcus and Dr. Mark Mengel discuss the decision to use premixed human insulin in the patient with noninsulin-dependent diabetes mellitus (NIDDM). Their discussion includes an analysis of the daily insulin needs of the patient and the glycemic control that may be achieved by providing a balanced mixture of intermediate-acting and short-acting insulin. Clinical experience with various regimens is discussed and evaluated along with the metabolic and pharmacokinetic factors that influence clinician prescribing preferences. Common pitfalls that can be avoided by using premixed human insulin are described. The study guide includes a post-test quiz for earning Continuing Medical Education (CME) credit. 4 references. (AA-M).

Bibliography: Multimedia on Insulin The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in insulin (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on insulin: •

Applications of insulin and growth hormone serum assays in clinical medicine [motion picture] Source: Emory University School of Medicine and National Medical Audiovisual Center; Year: 1969; Format: Motion picture; Atlanta: The Center: [for loan by National Medical Audiovisual Center; Washington: for sale by National Audiovisual Center], 1969

•

Conversion to U-100 insulin [slide]: a self-instructional program Source: Diane Billings, Sandra Monical; Year: 1975; Format: Slide; Indianapolis: Eli Lilly, 1975

•

Hyperglycemia (DKA) in the diabetes unit [videorecording]: I.V. insulin Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1981; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1981

Multimedia 329

•

Insulin [filmstrip] Source: Medical Electronic Educational Services, in cooperation with Western Wisconsin Technical Institute; Year: 1977; Format: Filmstrip; La Crosse, WI: The Institute, c1977

•

Insulin and oral hypoglycemic agents [videorecording] Source: Wayne State University, Directions for Education in Nursing via Technology; [produced by] CIT-TV, Wayne State University; Year: 1974; Format: Videorecording; Detroit: The University: [for loan and sale by Wayne State University, Systems, Distribution and Utilization], c1974

•

Insulin delivery system in diabetes mellitus [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1982; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1982

•

Problems of control in insulin treated diabetes [slide] Source: [Ohio Medical Education Network]; Year: 1980; Format: Slide; [Columbus, Ohio]: The Network, 1980

•

The Teaching nurse's role in the desensitization process: to insulin [sound recording] Source: Western New York Diabetes Educators; Year: 1976; Format: Sound recording; Buffalo: Communications in Learning, 1976

•

Treatment of insulin dependent diabetes [filmstrip] Source: Trainex Corporation; Year: 1977; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1977

•

What is insulin dependent diabetes [filmstrip] Source: Trainex Corporation; Year: 1977; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1977

331

CHAPTER 9. PERIODICALS AND NEWS ON INSULIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover insulin.

News Services and Press Releases One of the simplest ways of tracking press releases on insulin is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “insulin” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to insulin. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “insulin” (or synonyms). The following was recently listed in this archive for insulin: •

Upregulation of insulin receptor substrate-2 may help prevent or treat diabetes Source: Reuters Medical News Date: November 28, 2003

•

Fiber does not explain rye bread's insulin effect Source: Reuters Health eLine Date: November 24, 2003

332 Insulin

•

Myocyte PPAR-gamma plays key role in insulin resistance Source: Reuters Medical News Date: November 18, 2003

•

Alcohol consumption after eating reduces insulin levels Source: Reuters Medical News Date: November 17, 2003

•

Inhaled insulin suitable for type 2 diabetes not controlled by oral drugs Source: Reuters Medical News Date: October 27, 2003

•

Inhaled insulin good option for some diabetics Source: Reuters Health eLine Date: October 27, 2003

•

Inhaled insulin provides predictable dose in type 2 diabetics Source: Reuters Medical News Date: October 16, 2003

•

Inhaled insulin for diabetes gives reliable dose Source: Reuters Health eLine Date: October 16, 2003

•

Hyperglycemia, not hypoinsulinemia, affects ICU outcomes Source: Reuters Medical News Date: October 14, 2003

•

Insulin improves exercise performance in diabetics with heart failure Source: Reuters Medical News Date: September 29, 2003

•

CORRECTION: Obstructive sleep apnea may impair insulin sensitivity in obesity Source: Reuters Medical News Date: September 22, 2003

•

Insulin pump comparable to injections for type 2 diabetics Source: Reuters Medical News Date: August 26, 2003

•

Insulin pump as good as shots for diabetes Source: Reuters Health eLine Date: August 26, 2003

•

Peroxisome receptor tied to insulin sensitivity in mice Source: Reuters Medical News Date: August 25, 2003

•

Long-acting insulin Lantus lowers glucose without hypoglycemia risk Source: Reuters Medical News Date: August 25, 2003

•

Rosiglitazone reduces hyperinsulinemia in type 2 diabetics Source: Reuters Medical News Date: August 20, 2003

•

CORRECTED: Insulin beats oral drug for early adult diabetes Source: Reuters Health eLine Date: August 20, 2003

Periodicals and News

333

•

Insulin beats glibenclamide in early diabetes treatment Source: Reuters Medical News Date: August 19, 2003

•

Body builders warned of danger of abusing insulin Source: Reuters Health eLine Date: August 05, 2003

•

DHEA use enhances endothelial function and insulin sensitivity in me Source: Reuters Medical News Date: July 25, 2003

•

UK delays insulin pump introduction Source: Reuters Medical News Date: July 23, 2003

•

Roche gets FDA warning on insulin pump plant Source: Reuters Medical News Date: July 15, 2003

•

RAS blockade improves insulin sensitivity in essential hypertension Source: Reuters Medical News Date: July 15, 2003

•

Combined glucose monitor and insulin pump approved by FDA Source: Reuters Medical News Date: July 07, 2003

•

Insulin raises CSF amyloid levels in humans Source: Reuters Medical News Date: June 26, 2003

•

Weight loss tied to decrease in inflammatory proteins, improved insulin resistance Source: Reuters Medical News Date: June 24, 2003

•

Small study suggests insulin-Alzheimer's link Source: Reuters Health eLine Date: June 23, 2003

•

Insulin pump therapy lowers HbA1c more than insulin glargine in diabetic children Source: Reuters Medical News Date: June 18, 2003

•

Insulin glargine reduces risk of nocturnal hypoglycemia in type 2 diabetics Source: Reuters Medical News Date: June 18, 2003

•

Study sheds clues on female insulin skippers Source: Reuters Health eLine Date: June 17, 2003

•

Starting insulin therapy appears to increase risk of CHF Source: Reuters Medical News Date: June 17, 2003

•

Oral insulin does not prevent development of diabetes in at-risk subjects Source: Reuters Medical News Date: June 16, 2003

334 Insulin

•

Oral insulin does not keep diabetes at bay: study Source: Reuters Health eLine Date: June 16, 2003

•

One in four say "no way" to insulin shots: study Source: Reuters Health eLine Date: June 16, 2003

•

Inhaled insulin product proves safe Source: Reuters Health eLine Date: June 16, 2003

•

Some diabetic patients OK without insulin: study Source: Reuters Health eLine Date: June 02, 2003

•

Phase I trial of insulin delivery patch started Source: Reuters Medical News Date: May 28, 2003

•

Estrogen and raloxifene have differing effects on insulin sensitivity in older women Source: Reuters Medical News Date: May 20, 2003 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “insulin” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests.

Periodicals and News

335

Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “insulin” (or synonyms). If you know the name of a company that is relevant to insulin, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “insulin” (or synonyms).

Newsletters on Insulin Find newsletters on insulin using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go to the following hyperlink: http://chid.nih.gov/detail/detail.html. Limit your search to “Newsletter” and “insulin.” Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter.” Type “insulin” (or synonyms) into the “For these words:” box. The following list was generated using the options described above: •

Diabetes: Nutrition Guidelines Emphasize Personal Touch Source: Mayo Clinic Health Letter. 12(8): 4-5. August 1994. Contact: Available from Mayo Clinic Health Letter. Subscription Services, P.O. Box 53889, Boulder, CO 80322-3889. (800) 333-9037. Summary: This brief newsletter article reports on the new set of nutrition guidelines for people with diabetes. The guidelines, recently released by the American Diabetes Association (ADA), underscore the important role of diet in keeping blood glucose levels under control. The new recommendations stress the need for individualizing the diet and developing a meal plan based on the individual's food preferences, health concerns such as weight or blood cholesterol level, and insulin therapy. The article concludes by urging readers to work closely with a registered dietitian and other members of the diabetes care team in planning the diet.

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “insulin” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is

336 Insulin

updated every three months. The following is a typical result when searching for newsletter articles on insulin: •

Prostate Cancer, Abdominal Fat, and Insulin Source: AICR Science News. Issue 22. p. 2. December 2001. Contact: American Institute for Cancer Research. 1759 R Street NW, Washington, DC 20009. 202-328-7744. www.aicr.org. Summary: Excess abdominal fat could increase the risk for prostate cancer. High insulin levels might cause the body to store fat in this region. This Chinese case-control study, originally published in the Journal of the National Cancer Institute, investigated whether changes in insulin levels promotes prostate cancer risk. The study involved 128 prostate cancer patients and 306 controls. The results showed that those subjects with the highest blood levels of insulin had 2.5 times the prostate cancer risk of those with the lowest levels. Further research is required to define the precise nature of this association and to determine if insulin levels may be useful in predicting prostate cancer risk.

•

Insulin Analogues: Designer Insulins With Improved Characteristics for Better Patient Care Source: Diabetes News. 17(2): 5-7. 1996. Contact: Available from Excerpta Medica. P.O. Box 1126, 1000 BC Amsterdam, The Netherlands. Summary: In this article, the authors explore the present state of insulin development. After a brief section reviewing the history of insulin discovery and clinical use, the authors discuss alternative insulin delivery systems; insulin analogues; the oral delivery of insulin; insulin lispro (Humalog) and its clinical benefits; and a brief look at anticipated insulins of the future. References are available by request. 2 figures.

•

Insulin Pump Therapy in School-Aged Children with Diabetes: Experiences from Children's Hospital of Los Angeles Source: On the Cutting Edge. 22(6): 15-17. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Insulin pump therapy or continuous subcutaneous insulin infusion (CSII) has gained in acceptance for young school aged children with type 1 diabetes. At Children's Hospital of Los Angeles, patients and families are selected for insulin pump therapy if they have the appropriate skills, knowledge, and attitude. They must be able to determine how to correct an abnormal blood glucose level and understand why it occurred, count and dose for carbohydrate intake, compensate for changes in the daily routine, and follow care guidelines for sick days. As the child gets older, more and more responsibility for pump management is assumed by the child and relinquished by the parent. The authors of this article review these guidelines and note that there are no specific medical indications for CSII. If the patient and family have met the competency and psychological criteria, and desire to optimize basal and bolus therapy with an insulin pump, they should be afforded the opportunity since the advantages of CSII outweigh the risks. In the authors' experience, insulin pump therapy in school age children is an effective modality for improving diabetes outcome without negatively impacting on quality of life. 3 tables. 9 references.

Periodicals and News

•

337

Insulin Pump Therapy in Adolescents with Diabetes Source: On the Cutting Edge. 22(6): 18-21. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: The diabetes educator's obligation is to help teens fit diabetes into their lifestyles instead of fitting their lifestyles into their diabetes. The authors of this article on insulin pump therapy stress that diabetes educators must not lose sight of the ability of food to provide more than nutrients, especially for adolescents. To be successful, nutrition recommendations must be realistic and workable, without making major routine changes to those involved. Since a growing number of teens are initiating continuous subcutaneous insulin infusion (CSII), every attempt should be made to reflect the adolescent's food preferences and the family's social and cultural attitudes. Educators must strive to maintain the pleasures of the table while promoting normal healthy eating. Parents must introduce and promote healthy eating habits for the adolescent and the whole family while balancing the choices that CSII and carbohydrate counting allow. The authors also report on the 20 percent of the cohort of the Diabetes Control and Complications Trial (DCCT) who were adolescents between the ages of 13 and 19 years at entry. 12 references.

•

Influence of Carbohydrate Counting on Blood Glucose Pattern in Intensive Insulin Therapy in IDDM Source: On the Cutting Edge: Diabetes Care and Education. 17(4): 13-15. Summer 1996. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Chicago, IL 60606-6995. (312) 899-0040. Summary: This newsletter article addresses the influence of carbohydrate counting on blood glucose pattern in insulin-dependent diabetes mellitus (IDDM, or Type I) intensive therapy. The authors note that the quantification of carbohydrates, now known as CHO (carbohydrate) counting, provides a precise meal planning method with increased dietary flexibility. Topics include the three levels of carbohydrate counting, variables influencing blood glucose, prerequisites to establishing CHO, and predicting peak insulin activity. Detailed food, blood glucose (BG), physical activity, and medication records allow the clinician and the client to recognize BG patterns for safe insulin dose adjustments. The authors remind readers that it is particularly important to control for variables which include insulin action, premeal delays, injection site, physical activity, stress, intercurrent illness, and CHO counting. The article includes three case studies. 2 tables. 9 references. (AA-M).

Academic Periodicals covering Insulin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to insulin. In addition to these sources, you can search for articles covering insulin that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.”

338 Insulin

If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

339

CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for insulin. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with insulin. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

340 Insulin

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to insulin: Acarbose •

Systemic - U.S. Brands: Precose http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203498.html

Angiotensin-Converting Enzyme (Ace) Inhibitors •

Systemic - U.S. Brands: Accupril; Aceon; Altace; Capoten; Lotensin; Mavik; Monopril; Prinivil; Univasc; Vasotec 4; Zestril http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202044.html

Antidiabetic Agents, Sulfonylurea •

Systemic - U.S. Brands: Amaryl; DiaBeta; Diabinese; Dymelor; Glucotrol; Glucotrol XL; Glynase PresTab; Micronase; Orinase; Tolinase http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202742.html

Diazoxide •

Oral - U.S. Brands: Proglycem http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202191.html

Glyburide and Metformin •

Systemic - U.S. Brands: Glucovance http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500237.html

Insulin •

Systemic - U.S. Brands: Humulin 50/50; Humulin 70/30; Humulin 70/30 Pen; Humulin L; Humulin N; Humulin N Pen; Humulin R; Humulin R, Regular U500 (Concentrated); Humulin U; Lente; Lente Iletin II; Novolin 70/30; Novolin 70/30 PenFill; Novolin 70/30 Prefilled; Novolin L; Novoli http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203298.html

Insulin Aspart •

Systemic - U.S. Brands: NovoLog http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500253.html

Insulin Glargine •

Systemic - U.S. Brands: Lantus http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500147.html

Insulin Lispro •

Systemic - U.S. Brands: Humalog http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203622.html

Metformin •

Systemic - U.S. Brands: Glucophage http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202756.html

Researching Medications

341

Miglitol •

Systemic - U.S. Brands: Glyset http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500231.html

Nateglinide •

Systemic - U.S. Brands: Starlix http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500277.html

Octreotide •

Systemic - U.S. Brands: Sandostatin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202421.html

Pioglitazone •

Systemic - U.S. Brands: Actos http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500036.html

Repaglinide •

Systemic - U.S. Brands: Prandin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203463.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter,

342 Insulin

Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

343

APPENDICES

345

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute13: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

13

These publications are typically written by one or more of the various NIH Institutes.

346 Insulin

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

Physician Resources

347

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:15 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

14

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 15 See http://www.nlm.nih.gov/databases/databases.html.

348 Insulin

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “insulin” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “insulin” (or synonyms) into the “For these words:” box. The following is a sample result: •

Reassessment of External Insulin Infusion Pumps Source: Rockville, MD: Agency for Health Care Policy and Research. 1991. 12 p. Contact: Available from Agency for Health Care Policy and Research. Division of Information and Publications, 5600 Fishers Lane, Parklawn Building, Room 18-12, Rockville, MD 20857. (301) 443-4100. PRICE: Single copy free. Order Number: DHHS Pub. No. AHCPR 91-0030. Summary: Continuous subcutaneous insulin infusion (CSII) therapy using external infusion pumps provides an alternative to multiple daily injections (MDI) for people with insulin-dependent diabetes mellitus (IDDM) who require intensive insulin therapy. This report presents a reassessment of external insulin infusion pumps. The benefits cited for people on CSII include greater lifestyle flexibility with regard to meal timing, work, and recreational scheduling. The higher risks associated with CSII such as diabetic ketoacidosis, hypoglycemia, and skin problems may be averted with improvements in the mechanical design of CSII devices. The authors conclude that the overall clinical evidence indicates that CSII is as effective as MDI in attaining normoglycemia in people with IDDM who require intensive insulin therapy. 1 table. 44 references. (AA-M).

•

Insulin-Using Commercial Motor Vehicle Drivers Source: Washington, DC: Federal Highway Administration, U.S. Department of Transportation. 1991. 140 p. Contact: Available from United States Department of Commerce. National Technical Information Services, 5285 Port Royal Road, Springfield, VA 22161. (703) 487-4690. PRICE: $26 plus $3 shipping and handling. Publication Number FHWA-MC-92012. Order Number: PB92-183003. Summary: This document presents the report of the Office of Motor Carriers on their review of the current medical standard covering commercial motor vehicle (CMV) drivers with diabetes mellitus. The Standard (49 C.F.R. Section 391.41(b) (3)) permits qualification of individuals to drive a commercial motor vehicle if that person has no established medical history or clinical diagnosis of diabetes mellitus currently requiring

Physician Resources

349

insulin for control. A literature review of accidents involving drivers with diabetes was conducted along with a review of the current state laws regulating insulin-using CMV drivers. The effectiveness of current diabetes treatment is presented. A risk assessment was developed and applied to the information available concerning insulin-using drivers. Public comments submitted to the FHWA on this issue are tallied and summarized. The role of a medical advisory board in individual petitions, development of regulations, and the establishment of monitoring procedures is also discussed. 23 tables. 102 references. (AA-M)>

The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “insulin” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 208860 1532 913 399 34 211738

HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by “insulin” (or synonyms) at the following Web site: http://text.nlm.nih.gov. 16

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

17

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 18 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 19 20

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

350 Insulin

Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Insulin In the following section, we will discuss databases and references which relate to the Genome Project and insulin. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 21 Adapted 22

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

Physician Resources

351

To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “insulin” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for insulin: •

Acute Insulin Response Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601676

•

Bird-headed Dwarfism with Progressive Ataxia, Insulin-resistant Diabetes, Goiter, and Primary Gonadal Insufficiency Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210740

•

Delayed-early Insulin-induced Gene Cl-6 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600913

•

Diabetes Mellitus, Insulin-dependent Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?222100

•

Diabetes Mellitus, Insulin-dependent, 10 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601942

•

Diabetes Mellitus, Insulin-dependent, 11 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601208

•

Diabetes Mellitus, Insulin-dependent, 12 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601388

•

Diabetes Mellitus, Insulin-dependent, 13 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601318

•

Diabetes Mellitus, Insulin-dependent, 15 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601666

•

Diabetes Mellitus, Insulin-dependent, 17 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?603266

•

Diabetes Mellitus, Insulin-dependent, 18 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?605598

•

Diabetes Mellitus, Insulin-dependent, 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?125852

•

Diabetes Mellitus, Insulin-dependent, 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600318

•

Diabetes Mellitus, Insulin-dependent, 4 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600319

•

Diabetes Mellitus, Insulin-dependent, 5 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600320

•

Diabetes Mellitus, Insulin-dependent, 6 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601941

•

Diabetes Mellitus, Insulin-dependent, 7 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600321

•

Diabetes Mellitus, Insulin-dependent, 8 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600883

352 Insulin

•

Diabetes Mellitus, Insulin-dependent, X-linked, Susceptibility to Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300136

•

Diabetes Mellitus, Insulin-resistant, with Acanthosis Nigricans and Hypertension Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?604367

•

Diabetes Mellitus, Noninsulin-dependent Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?125853

•

Diabetes Mellitus, Noninsulin-dependent, 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601283

•

Diabetes Mellitus, Noninsulin-dependent, 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601407

•

Diabetes Mellitus, Noninsulin-dependent, 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?603694

•

Fasting Glucose and Specific Insulin Levels Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606035

•

Hyperinsulinism-hyperammonemia Syndrome Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606762

•

Insulin Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176730

•

Insulin Activator Factor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?605346

•

Insulin Promoter Factor 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600733

•

Insulin Receptor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147670

•

Insulin Receptor Gene Transcription Factor 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601043

•

Insulin Receptor Gene Transcription Factor 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601044

•

Insulin Receptor Substrate 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147545

•

Insulin Receptor Substrate 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600797

•

Insulin Receptor Substrate 4 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?603510

•

Insulin Receptor-related Receptor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147671

•

Insulin Receptors, Familial Increase in Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147320

•

Insulin-degrading Enzyme Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146680

•

Insulin-induced Gene 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602055

Physician Resources

353

•

Insulin-like 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146738

•

Insulin-like 4 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600910

•

Insulin-like 5 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606413

•

Insulin-like 6 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606414

•

Insulin-like Dna Sequence Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147490

•

Insulin-like Growth Factor I Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147440

•

Insulin-like Growth Factor I Receptor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147370

•

Insulin-like Growth Factor I, Resistance to Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?243095

•

Insulin-like Growth Factor Ii Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147470

•

Insulin-like Growth Factor Ii Receptor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147280

•

Insulin-like Growth Factor-binding Protein 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146730

•

Insulin-like Growth Factor-binding Protein 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146731

•

Insulin-like Growth Factor-binding Protein 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146732

•

Insulin-like Growth Factor-binding Protein 4 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146733

•

Insulin-like Growth Factor-binding Protein 5 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146734

•

Insulin-like Growth Factor-binding Protein 6 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146735

•

Insulin-like Growth Factor-binding Protein 7 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602867

•

Insulin-like Growth Factor-binding Protein, Acid-labile Subunit Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601489

•

Insulin-related Dna Polymorphism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147510

•

Persistent Hyperinsulinemic Hypoglycemia of Infancy Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601820

•

Pineal Hyperplasia, Insulin-resistant Diabetes Mellitus, and Somatic Abnormalities Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262190

354 Insulin

•

Pseudoacromegaly with Severe Insulin Resistance Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602511 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

•

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell

Physician Resources

355

anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “insulin” (or synonyms) into the search box and click “Go.”

356 Insulin

Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “insulin” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

25

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 26 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

357

APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on insulin can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to insulin. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to insulin. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “insulin”:

358 Insulin

•

Other guides Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html Diabetes and Pregnancy http://www.nlm.nih.gov/medlineplus/diabetesandpregnancy.html Diabetic Diet http://www.nlm.nih.gov/medlineplus/diabeticdiet.html Juvenile Diabetes http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html Metabolic Syndrome X http://www.nlm.nih.gov/medlineplus/metabolicsyndromex.html Ovarian Cysts http://www.nlm.nih.gov/medlineplus/ovariancysts.html Pancreas Transplantation http://www.nlm.nih.gov/medlineplus/pancreastransplantation.html

Within the health topic page dedicated to insulin, the following was listed: •

General/Overviews Diabetes http://www.fda.gov/opacom/lowlit/diabetes.html Diabetes http://www.nlm.nih.gov/medlineplus/tutorials/diabetesintroductionloader.html Diabetes: A Growing Public Health Concern Source: Food and Drug Administration http://www.fda.gov/fdac/features/2002/102_diab.html What is Diabetes? http://www.ncfh.org/pateduc/en-diabetes.htm

•

Diagnosis/Symptoms A1C Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/a1c/test.html Diabetes: Assessing Your Risk Source: American Academy of Family Physicians http://familydoctor.org/handouts/347.html Diagnosis of Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/diagnosis/index.htm Glucose Tests Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/glucose/test.html

Patient Resources

359

Microalbumin Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/microalbumin/test.html Oral Glucose Tolerance Test Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/oralglu.pdf Serum Creatinine Test Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=SA00007 •

Treatment Diabetes Pills Source: Food and Drug Administration http://www.fda.gov/diabetes/pills.html Diabetes: New Treatments Source: American Academy of Family Physicians http://familydoctor.org/handouts/388.html Giving a Subcutaneous Injection Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf Medicines for People with Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm Oral Diabetes Medications Source: American Diabetes Association http://www.diabetes.org/type2/medical/oralmeds.jsp

•

Alternative Therap Alternative Therapies for Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/alternativetherapies/index.htm

•

Coping Coping with Diabetes Complications Source: American Diabetes Association http://www.diabetes.org/info/complications/other/default.jsp Diabetes: Helping a Family Member Who Has Diabetes Source: American Academy of Family Physicians http://familydoctor.org/handouts/353.html Q&A: Lifestyle Adjustments When You Have Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00018 Tips for Helping a Person with Diabetes Source: National Diabetes Education Program http://www.ndep.nih.gov/diabetes/pubs/TipsHelping_Eng.pdf

360 Insulin

•

Specific Conditions/Aspects Alcohol Source: American Diabetes Association http://www.diabetes.org/health/nutrition/alcohol/alcohol.jsp Aspirin Therapy for People with Diabetes Source: American Diabetes Association http://www.diabetes.org/main/info/aspirin.jsp Blood Pressure Control in People with Type 2 Diabetes Recommendations from the American College of Physicians Source: American College of Physicians http://www.annals.org/cgi/content/full/138/7/I-70

Mellitus:

Cholesterol, Triglycerides, and Diabetes http://www.diabetes.org/main/uedocuments/ADACholesterolPatient.pdf Depression and Diabetes Source: National Institute of Mental Health http://www.nimh.nih.gov/publicat/depdiabetes.cfm Diabetes and Common Mouth Problems Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00013 Diabetes and Vaccines Source: Centers for Disease Control and Prevention http://www.cdc.gov/nip/vacsafe/concerns/Diabetes/default.htm Diabetes in African Americans Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/africanamerican/index.htm Diabetes in American Indians and Alaska Natives Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/americanindian/index.htm Diabetes in Asian and Pacific Islander Americans Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/asianamerican/index.htm Diabetes in Hispanic Americans Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/hispanicamerican/index.htm Diabetic Arthritis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00526 Diabetic Coma: A Serious but Controllable Condition Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00022 Financial Help for Diabetes Care Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/financialhelp/index.htm

Patient Resources

361

Frequently Asked Questions about Importing Beef Insulin for Personal Use Source: Center for Drug Evaluation and Research http://www.fda.gov/cder/drug/beefinsulin/default.htm Gastroparesis and Diabetes Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/gastroparesis/index.htm High Blood Pressure and Diabetes Source: American Diabetes Association http://www.diabetes.org/main/uedocuments/HighBloodPressure-English.pdf Hyperglycemia (High Blood Sugar) Source: American Diabetes Association http://www.diabetes.org/type2/medical/hyperglycemia/default.jsp Hyperinsulinemia Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00896 Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS) Source: American Diabetes Association http://www.diabetes.org/type2/medical/HHNS.jsp If You Have Diabetes, Talk to Your Doctor about Your Increased Risk for Heart Disease and Stroke http://www.diabetes.org/main/uedocuments/ADALinkQA.pdf Insulin Resistance and Pre-Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/index.htm JAMA Patient Page: Safe Driving for People with Diabetes Source: American Medical Association http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZRHSKYMA C&sub_cat=268 Liver Disease and Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00193 Medicare Coverage of Diabetes Related Supplies and Services Source: Centers for Medicare & Medicaid Services http://www.medicare.gov/Health/Diabetes.asp Pima Indians: Pathfinders for Health Source: National Institute of Diabetes and Digestive and Kidney Diseases http://diabetes.niddk.nih.gov/dm/pubs/pima/index.htm Prevent Diabetes Problems: Keep Your Heart and Blood Vessels Healthy Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/complications_heart/index.htm Prevent Diabetes Problems: Keep Your Teeth and Gums Healthy Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/complications_teeth/index.htm

362 Insulin

Skin Care Source: American Diabetes Association http://www.diabetes.org/main/health/body_care/skin/default.jsp Stress Source: American Diabetes Association http://www.diabetes.org/health/stress/stress.jsp Take Care of Your Heart. Manage Your Diabetes Source: National Diabetes Education Program http://www.ndep.nih.gov/diabetes/pubs/TCH_AsAm_flyer_Eng.pdf What Is Hypoglycemia? (Low Blood Sugar) Source: American Diabetes Association http://www.diabetes.org/type2/medical/hypoglycemia/default.jsp When You're Sick Source: American Diabetes Association http://www.diabetes.org/type2/living/sick/default.jsp •

Children Diabetes in Children and Adolescents Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/youth/youth_FS.htm MEDLINEplus: Juvenile Diabetes Source: National Library of Medicine http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html Tips for Kids with Type 2 Diabetes: Be Active Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/Youth_Tips_Active.pdf Tips for Kids with Type 2 Diabetes: What Is Diabetes? Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/Youth_Tips_Diabetes.pdf

•

From the National Institutes of Health 7 Principles for Controlling Your Diabetes for Life Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/control/principles.htm Diabetes Overview Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm Your Guide to Diabetes: Type 1 and Type 2 Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/type1and2/index.htm

•

Journals/Newsletter Diabetes Dateline Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/health/diabetes/dateline/index.htm

Patient Resources

•

363

Latest News Buckwheat Holds Promise for Diabetes Source: 11/25/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14836 .html Cinnamon May Cut Blood Sugar Levels Source: 11/25/2003, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14842 .html Diabetes Drug Not Linked to Lactic Acid Problem Source: 11/26/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14874 .html HHS Releases 2003 National Diabetes Estimates Source: 11/13/2003, Dept. of Health and Human Services http://www.hhs.gov/news/press/2003pres/20031113.html High Risk of Narrowed Blood Vessels in Legs for People with Diabetes Source: 11/21/2003, American Diabetes Association http://ada.yellowbrix.com/pages/ada/Story.nsp?story_id=43948162&ID=ada More News on Diabetes http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_d.html#D iabetes Prevalence of Self-Reported Heart Disease and Stroke among U.S. Adults with and without Diabetes Source: 11/06/2003, Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/fs031106.htm

•

Law and Policy Fighting Discrimination Based on Diabetes Source: American Diabetes Association http://www.diabetes.org/main/community/advocacy/discrimination.jsp Traveling with Diabetes Supplies Source: American Diabetes Association http://www.diabetes.org/main/community/advocacy/travel.jsp

•

Men Diabetes Can Affect Men's Sexual Health http://www.diabetes.org/main/uedocuments/Channel16-Men.pdf Diabetes Facts & Figures among Men Source: American Diabetes Association http://www.diabetes.org/info/facts/facts_men.jsp Erectile Dysfunction in Diabetes: Keys to Prevention Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00045

364 Insulin

•

Organizations American Diabetes Association http://www.diabetes.org/ CDC's Diabetes Public Health Resource Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/ National Diabetes Education Program http://ndep.nih.gov/ National Diabetes Information Clearinghouse Source: National Institute of Diabetes and Digestive and Kidney Diseases http://diabetes.niddk.nih.gov/ National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/

•

Prevention/Screening Am I at Risk for Type 2 Diabetes? Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/riskfortype2/index.htm Lipid Panel Test: Gauging Your Heart Disease Risk Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=SA00006 Task Force Issues Two Recommendations on Screening for Diabetes in Adults and Pregnant Women Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2003/diabscpr.htm Your Game Plan for Preventing Type 2 Diabetes Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/GP_Booklet.pdf

•

Research Blood Pressure Drug Losartan Appears to Benefit the Kidneys of People with Type 2 Diabetes Who Do Not Have High Blood Pressure Source: American College of Physicians http://www.annals.org/cgi/content/full/139/2/I-24 Comparison of Three Insulin Regimens.for Treating Type 2 Diabetes Source: American College of Physicians http://www.annals.org/cgi/content/full/138/12/I-33 Diabetes and Hypertension Combo Invite Silent Stroke Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3015383 Diabetes Control and Complications Trial (DCCT) Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/control/index.htm

Patient Resources

365

Diabetes Prevention Program Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/preventionprogram/index.htm Diabetes Prevention Program: Questions and Answers Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/patient/dpp/dpp-q&a.htm Diabetic Women Gain Significant Health Benefits from Eating Fish Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3010518 Eating Breakfast May Reduce Risk of Obesity, Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009715 Heart Health Should Be the Front Line of Diabetes Care Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3002623 Less Fit Teens More Likely to Have Precursor to Diabetes Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009762 Lower Blood Pressure Decreases Heart Attack Risk in Diabetics with Clogged Leg Arteries Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3007755 Many Obese Youth Have Condition That Precedes Type 2 Diabetes Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/mar2002/nichd-13.htm Men with 3 of 5 Metabolic Abnormalities Risk Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3013637 NIH Reports Progress in Diabetes Research Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/welcome/releases/10-23-02.htm Postmenopausal Hormone Therapy and Blood Sugar Source: American College of Physicians http://www.annals.org/cgi/content/full/138/1/I-10 Short Thighs Linked to Greater Likelihood of Diabetes Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009764 Study Examines Cost-Effectiveness of Treatment Interventions for Type 2 Diabetes Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r020514.htm Use of Common Laboratory Tests to Identify People with Insulin Resistance Source: American College of Physicians http://www.annals.org/cgi/content/full/139/10/I-16

366 Insulin

•

Statistics Diabetes and Women's Health Across the Life Stages: A Public Health Perspective Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/pubs/women/index.htm Diabetes: Disabling, Deadly, and on the Rise http://www.cdc.gov/nccdphp/aag/aag_ddt.htm Eliminate Disparities in Diabetes Source: Centers for Disease Control and Prevention, Office of Minority Health http://www.cdc.gov/omh/AMH/factsheets/diabetes.htm FASTATS: Diabetes Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/diabetes.htm HHS Issues Report Charting Steady Gains in Americans' Health, Though Diabetes Remains Growing Concern Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r031003.htm National Diabetes Statistics Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm New State Data Show Obesity and Diabetes Still On the Rise Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r021231.htm Pre-Diabetes in the United States in 2000 Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/pubs/factsheets/prediabetes.htm Prevalence of Self-Reported Heart Disease and Stroke among U.S. Adults with and without Diabetes Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/fs031106.htm Preventing Diabetes and Its Complications Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/nccdphp/pe_factsheets/pe_ddt.htm Study Shows Sharp Rise in the Cost of Diabetes Nationwide Source: Dept. of Health and Human Services http://www.os.dhhs.gov/news/press/2003pres/20030227a.html

•

Teenagers Diabetes in Children and Adolescents Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/youth/youth_FS.htm

•

Women Diabetes Can Affect Women's Sexual Health http://www.diabetes.org/main/uedocuments/Channel15-Women.pdf

Patient Resources

367

Diabetes Facts & Figures among Women Source: American Diabetes Association http://www.diabetes.org/info/facts/facts_women.jsp Menopause and Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00038 Overcoming the Challenges of Blood Sugar Control during Menstruation Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00041 You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on insulin. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Insulin Source: Cleveland, OH: Diabetes Association of Greater Cleveland. 2001. 2 p. Contact: Available from Diabetes Association of Greater Cleveland. 3601 South Green Road Suite 100, Cleveland, Ohio 44122. (216) 591-0800 Fax (216) 591-0320. E-mail: [email protected]. Website: www.dagc.org. PRICE: Single copy free. Summary: Insulin is a hormone that helps the body use glucose (sugar) for energy. People with type 1 diabetes must take insulin to survive. Sometimes people with type 2 diabetes take insulin because they need more insulin than their pancreas is able to make. This fact sheet describes the use of insulin to treat diabetes. Topics include where insulin comes from, why insulin has to be injected, the six types of insulin, how much insulin to take, how often insulin is injected, and insulin storage. One chart outlines the six types of insulin: rapid acting (lispro), short acting (regular), intermediate acting (NPH or lente), long acting (ultralente), premixed (NPH and regular), and basal (glargine). The fact sheet concludes with the contact information for the Diabetes Association of Greater Cleveland (www.dagc.org). 1 table. 1 reference.

•

Is an Insulin Pump Right for Your Child and Family? Source: Diabetes Spectrum. 14(2): 90. May 1, 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org.

368 Insulin

Summary: This article provides parents of children with type 1 diabetes with guidelines for determining whether insulin pump therapy is the right choice for them. Insulin pumps are attached to the body by a needle placed under the skin. Pump therapy delivers rapid or short acting insulin continuously through the needle. In addition to providing basal insulin throughout the day, pumps are programmed to deliver additional insulin with each meal and snack. Although pumps can improve diabetes control and give children more flexibility, very young children cannot manage their own pumps, and older children need a great deal of help from parents. Thus, a knowledgeable parent or caregiver must be available 24 hours a day, 7 days a week. The article lists questions parents can ask themselves to determine whether pump therapy is a good fit for their child and family. •

Diabetes: Flexible Insulin Regimens for People with Type 1 Diabetes Source: American Family Physician. 62(9): 2144. November 1, 2000. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This article uses a question and answer format to provide people who have type 1 diabetes with information on flexible insulin regimens. Insulin is a hormone that controls the level of glucose in the body. People who have type 1 diabetes do not make enough insulin, so glucose builds up in their blood. Over time, high blood glucose levels can cause serious health problems. Insulin can be administered with a syringe, an insulin pen, or an insulin pump. A flexible insulin regimen allows a person to adjust the timing and amount of insulin to meet his or her needs. Although a flexible insulin regimen has benefits, it means that a person will have to check his or her blood glucose levels regularly, keep track of what he or she eats, and learn how his or her body reacts to insulin and how to adjust the dose.

•

Drawing and Injecting Insulin. Extraccion e Inyeccion de Insulina Source: Franklin Lakes, NJ: Becton Dickinson. 1993. 11 p. Contact: Available from Becton Dickinson and Company. Consumer Products Division, One Becton Drive, Franklin Lakes, NJ 07417-1883. (800) 526-4650 or (201) 847-7100. PRICE: Free. Summary: This bilingual pamphlet uses color photographs to illustrate insulin injection techniques. Sterile procedures, syringe filling injection, and proper syringe disposal are depicted.

•

Pattern Control: A Guide for Adjusting Your Insulin Doses Source: Minneapolis, MN: Park Nicollet Health Source. 1997. 30 p. Contact: Available from Park Nicollet Health Source. 3800 Park Nicollet Boulevard, Minneapolis, MN 55416. (800) 372-7776 or (612) 993-3534. Fax (612) 993-1840. PRICE: $2.95 for 1-9 copies; $2.65 for 10-99 copies; $2.35 for 100-499 copies. ISBN: 1885115458. Summary: This booklet is designed to help readers learn to recognize and correct a pattern of high or low blood glucose readings. The authors point out that pattern control is an important first step to gaining better control of blood glucose levels and more flexibility in life. Topics include how insulin works, personal insulin regimens, five steps to pattern control, monitoring insulin adjustments, and achieving better blood glucose control. The five steps to pattern control include knowing a target blood glucose range,

Patient Resources

369

testing and recording blood glucose levels, looking for patterns, determining which insulin to adjust, and making the insulin adjustment. The authors note that factors other than insulin may affect blood glucose levels. Eating more than usual, exercising less than usual, experiencing emotional or physical stress, being ill or having an infection, and taking other medications that affect blood glucose may cause blood glucose levels to increase. Blood glucose levels may decrease if a person eats less than usual, delays or skips a meal or snack, or is more active than usual. The booklet concludes with six practice exercises and two pages for recording personal insulin doses and blood glucose readings. Space for answers to the questions in each practice exercise is provided. For each exercise, the correct answers to the questions are provided at the bottom of the appropriate page. (AA-M). •

Insulin-Dependent Diabetes Source: Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 1994. 36 p. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Full-text available online at no charge; single copy free; bulk copies available. Summary: This booklet provides an overview of diabetes. Topics include a definition of the disease and the different types of diabetes; the causes of diabetes; the etiology and symptoms of insulin-dependent diabetes (IDDM); living with diabetes; handling diabetes-related emergencies; how diabetes affects the body and its metabolism; handling special situations, including illness and stress, surgery, pregnancy, and school and social activities; and current strategies in diabetes research. The booklet concludes with a brief list of resource organizations through which readers can obtain more information. The booklet is illustrated with black and white photographs of people with diabetes and health care providers. 2 figures.

•

Introduction to Insulin Pump Therapy Source: Sylmar, CA: Mini Med Technologies. 1993. 24 p. Contact: Available from Mini Med Technologies. 12744 San Fernando Road, Sylmar, CA 91342. (800) 933-3322. PRICE: Single copy free. Summary: This booklet was written for people who have just started pump therapy with the MiniMed Insulin Pump for the treatment of their insulin-dependent diabetes. It is also written for those who are thinking about starting pump therapy, but who want more information before making a decision. Part One provides a brief overview of pump therapy: what it is, why it was developed, who it is for, and some of the benefits it may provide. Part Two provides answers to many of the questions asked by people who have just started pump therapy or are considering doing so. These questions address issues such as sleeping, exercising and travelling with a pump, and caring for the infusion site. Part Three is a glossary of terms used frequently in the world of pump therapy. (AA-M).

•

Carbohydrate Counting: Using Carbohydrate/Insulin Ratios (Level 3) Source: Alexandria, VA, and Chicago, IL: American Diabetes Association and The American Dietetic Association. 1995. 32 p.

370 Insulin

Contact: Available from American Diabetes Association. Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (404) 442-9742. PRICE: $15 (members) or $18 (nonmembers) for package of 10 booklets plus accompanying professional information (2 pages). Order Number CCCL3. Also available from The American Dietetic Association. 216 W. Jackson Boulevard, Chicago, IL 60606-6995. (800) 877-1600, ext. 5000. Summary: This booklet, the most advanced in a series of three, builds on the basic concepts of carbohydrate counting and pattern management as introduced in the first two booklets. This booklet is designed for people who take insulin and who have chosen intensive diabetes management, using multiple daily injections (MDI) or an insulin pump. The booklet describes how the carbohydrate counting and pattern management skills can be used to adjust short-acting (Regular) insulin according to the carbohydrate eaten and physical activity. Topics include determining if the carbohydrate/insulin ratios system is appropriate for a particular individual; developing carbohydrate/insulin ratios; adjusting the carbohydrate/insulin ratios over time; adjusting insulin for dietary fats, fiber, and protein intake; and what to expect from the Registered Dietitian on the health care team. The booklet concludes with practice worksheets. The series is designed for people with IDDM, NIDDM, and gestational diabetes mellitus (GDM). 9 references. •

Traveling With Insulin Source: Indianapolis, IN: Eli Lilly and Company. 1994. 7 p. Contact: Available from Eli Lilly and Company. Lilly Corporate Center, Indianapolis, IN 46285. (800) 545-5979 or (317) 276-2000. PRICE: Single copy free. Summary: This brochure provides specific travel tips for people with diabetes. Tips are included for planning a trip, what to take, how to carry insulin, and how to prepare for traveling abroad. A chart is included listing the availability of 40- and 100-unit sizes of various insulins in a large number of countries. When traveling abroad, patients are advised to consult with their doctor before leaving, plan their trip carefully, and carry sufficient U-100 insulin and diabetes identification.

•

Preparing and Injecting Insulin Source: Indianapolis, IN: Eli Lilly and Company. 1994. 4 p. Contact: Available from Eli Lilly and Company. Lilly Corporate Center, Indianapolis, IN 46285. (800) 545-5979 or (317) 276-2000. PRICE: Single copy free. Summary: This brochure shows how to draw insulin into a syringe and give an insulin shot. The brochure takes the reader step by step through preparing a single dose of insulin, preparing a mixed dose of insulin, and giving the insulin shot. Each step is illustrated by a color photograph.

•

Human Insulin Source: Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc. 1992. 2 p. Contact: Available from Novo Nordisk Pharmaceuticals, Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Summary: This brochure, targeted at people with diabetes, reviews the various types of insulin on the market. Written in a question-and-answer format, topics include how insulin is made, how human insulin differs from animal insulin, how to read the labels

Patient Resources

371

of insulin boxes, any risks from using human insulin, care and storage of human insulin, and switching from animal to human insulin. Photographs depict each of five different insulin boxes. •

Diabetes and Insulin Injection Source: Cleveland, OH: Diabetes Association of Greater Cleveland. 1991. 20 p. Contact: Available from Diabetes Association of Greater Cleveland. 3601 S. Green Road, Cleveland, OH 44122. (216) 591-0800. PRICE: $2 plus shipping and handling. Summary: This brochure, written in easy-to-understand language, reviews the basics of diabetes and insulin injections. Topics include the basic types of insulin, brand names and types of insulins currently available, storing insulin, timing of injections, important facts about syringes, how to prepare and give insulin, injection sites, disposal of syringes, and mixing insulins. Step-by-step instructions for the actual preparation and injection are given, with line drawings illustrating each concept presented.

•

Insulin Dependent Diabetes Mellitus (IDDM) Source: West Hills, CA: Nutrition Prescriptives. 1996. 2 p. Contact: Available from Nutrition Prescriptives. P.O. Box 4417, West Hills, CA 91308. (818) 347-4760. Fax (818) 992-4319. PRICE: $10.00 for reproducible master copy. Order number: P9. Summary: This copier-ready, interactive counseling tool is designed to help health care professionals educate patients about type 1 diabetes. It provides an assessment and screening guide that allows health care professionals to check the patient's nutrition problems and record the date each problem was discussed. The tool is designed to facilitate discussion with the patient of possible eating behavior problems in the areas of quality, quantity, and frequency of intake. It points out that nutrition education goals include facilitating the patient's ability to both understand and apply type 1 diabetes nutrition principles. The importance of involving the patient as an active participant in the counseling process is stressed.

•

Balancing Insulin and Meals On A Night Work Schedule Source: Columbus, OH: Central Ohio Diabetes Association 199X. 1 p. Contact: Available From Central Ohio Diabetes Association (CODA). Janet Gorman, 1803 West Fifth Avenue, Columbus, OH 43212. (614) 486-7124; (800) 422-7946. PRICE: Single copy free. Summary: This fact sheet addresses the challenge faced by people with insulindependent diabetes who must work night shifts, balancing insulin injections and mealtimes with their work schedule. Four suggestions are presented and discussed: establishing consistency in the schedule; determining a regular meal pattern with the help of a dietitian; comparing the action of the insulin injections with the meal plan; and monitoring and adjusting the plan, including self monitoring of blood glucose.

•

Insulin Delivery to Match Insulin Need: Pharmacokinetics of Continuous Subcutaneous Insulin Delivery (CSII) Source: Sylmar, CA: Mini Med Technologies. 1993. 1 p.

372 Insulin

Contact: Available from Mini Med Technologies. 12744 San Fernando Road, Sylmar, CA 91342. (800) 933-3322. PRICE: Single copy free. Summary: This fact sheet describes the pharmacokinetics of continuous subcutaneous insulin delivery (CSII). The characteristics of CSII are outlined, including the elimination of the subcutaneous depot of insulin; predictable absorption; and a bimodal delivery that mimics the action of the pancreas. Four charts illustrate the metabolism of insulin as created by the normal pancreas with: two injections per day of NPH and regular insulin, four injections per day of Ultra-Lente and regular insulin, and the pump therapy (basal and bolus). 4 references. •

Insulin Pumps Source: Postgraduate Medicine. 101(2): 282. February 1997. Summary: This fact sheet describes the use of a continuous subcutaneous insulin infusion pump, a device that can provide people with diabetes a more near-normal way to keep their blood glucose levels in balance. The insulin pump consists of a pump in a plastic case that's about the size of a deck of cards. It contains a reservoir or cartridge holding several days' worth of insulin, a tiny battery-operated pump, and a computer chip regulating how much insulin is pumped. The infusion set is a thin plastic tube with a fine needle at the end. It carries the insulin from the pump to the site of infusion beneath the skin. The insulin pump delivers insulin in two ways: continuously at a low dose and rapidly in a larger dose. The larger, or 'bolus' doses are given before meals. The fact sheet also discusses some of the adaptations necessary to adjust to wearing an insulin pump. The fact sheet concludes that most people feel that the adjustments they have to make are minor and that having their diabetes well controlled makes the effort worthwhile. The fact sheet is designed to be photocopied and distributed to patients. 2 figures.

•

Diabetes Mellitus, Insulin-Dependent (Type I Diabetes; IDDM) Source: in Griffith, H.W. Instructions for Patients. 5th ed. Philadelphia, PA: W.B. Saunders Company. 1994. p. 121. Contact: Available from W.B. Saunders Company. Book Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. PRICE: $49.95. ISBN: 0721649300 (English); 0721669972 (Spanish). Summary: This fact sheet on insulin-dependent diabetes mellitus is from a compilation of instructions for patients, published in book format. The fact sheet provides information in three sections: basic information, including a description of the condition, frequent signs and symptoms, causes, risk factors, preventive measures, expected outcome, and possible complications; treatment, including general measures, medication, activity guidelines, and diet; and when to contact one's health care provider. The fact sheet can be photocopied and distributed to patients as a reinforcement of oral instructions and as a teaching tool. The book in which the fact sheet appears is available in English or Spanish.

•

Diabetes Mellitus, Non-Insulin-Dependent (Type II Diabetes; NIDDM) Source: in Griffith, H.W. Instructions for Patients. 5th ed. Philadelphia, PA: W.B. Saunders Company. 1994. p. 122.

Patient Resources

373

Contact: Available from W.B. Saunders Company. Book Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. PRICE: $49.95. ISBN: 0721649300 (English); 0721669972 (Spanish). Summary: This fact sheet on noninsulin-dependent diabetes mellitus is from a compilation of instructions for patients, published in book format. The fact sheet provides information in three sections: basic information, including a description of the condition, frequent signs and symptoms, causes, risk factors, preventive measures, expected outcome, and possible complications; treatment, including general measures, medication, activity guidelines, and diet; and when to contact one's health care provider. The fact sheet can be photocopied and distributed to patients as a reinforcement of verbal instructions and as a teaching tool. The book in which the fact sheet appears is available in English or Spanish. •

Insulin-Dependent Diabetes Mellitus (Type 1) Source: Detroit, MI: American Autoimmune Related Diseases Association. 199x. 4 p. Contact: Available from American Autoimmune Related Diseases Association. 15476 Gratiot Avenue, Detroit, MI 48205. (313) 371-8600. Fax (313) 371-6002. E-mail: [email protected]. PRICE: Single copy free. Summary: This fact sheet provides information about insulin-dependent diabetes mellitus (IDDM, or Type I). The fact sheet explains that in IDDM, autoantibodies formed by the immune system attack the beta cells of the pancreas, destroying their ability to make insulin. Researchers believe that one or more factors in the environment trigger the immune system to destroy insulin-producing cells; most, if not all, people with IDDM have inherited traits that put them at risk. Topics include autoimmunity; diabetes treatment; general diabetes complications; acute complications; long-term complications; kidney disease; heart disease; diabetic retinopathy; and diabetic neuropathy. Other topics include pregnancy in women with IDDM; genetics; illness and surgery; research in diabetes; and clinical trials. The authors point out that acute complications pose the greatest threat to survival in young people with IDDM. Longterm complications, which include diabetic nephropathy, heart disease, diabetic retinopathy, and diabetic neuropathies, become more important as people with IDDM grow older. The fact sheet concludes with a list of other autoimmune diseases, more information specific to autoimmunity, the role of the American Autoimmune Related Diseases Association, and a list of suggested resources. (AA-M).

•

U.S. Nationwide Survey of External Insulin Pump Use Source: Sylmar, CA: Mini Med Technologies. 1991. 2 p. Contact: Available from Mini Med Technologies. 12744 San Fernando Road, Sylmar, CA 91342. (800) 933-3322. PRICE: Single copy free. Summary: This fact sheet summarizes a nationwide survey of insulin pump use in 1015 patients using continuing subcutaneous insulin infusion (CSII). The questionnaire investigated patient reasons for initiation and continuation of CSII; efficacy of treatment as reflected by self-reported glycosylated hemoglobin levels; pump training and selfcare practices of users; and frequency of pump-related complications. Results show that longer initial pump training involving a physician with a team was reported to be more useful and with better eventual outcome. CSII users reported a low rate of complications and were very satisfied with the increased flexibility pump therapy provided. The fact sheet is presented in chart form, 11 by 16 inches in size. 5 figures.

374 Insulin

•

Insulin Resistance Syndrome Source: American Family Physician. 63(6): 1165-1166. March 15, 2001. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This fact sheet uses a question and answer format to provide people who have insulin resistance syndrome with information on the diagnosis and treatment of the syndrome. Insulin resistance occurs when the tissues stop responding to insulin, allowing insulin to accumulate in the blood. There is no test for insulin resistance syndrome, but a doctor may suspect the syndrome in a patient who has a history of diabetes in first degree relatives; patients with a personal history of gestational diabetes, polycystic ovary syndrome, or impaired glucose tolerance; and obese patients, particularly those with abdominal obesity. Insulin resistance syndrome may be prevented by maintaining a healthy weight, exercising, and eating a lot of dietary fiber. 1 figure. 1 table.

•

All About Insulin Source: Alexandria, VA: American Diabetes Association. 1994. 4 p. Contact: Available from American Diabetes Association, Inc. Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. PRICE: $9.95 (members), $11.95 (nonmembers) for 50 copies; single copy free. Order number CDBD13. Summary: This fact sheet, which is one in a series of 42 fact sheets about daily living and coping with diabetes, provides detailed information on insulin. Topics include insulin composition, types, strengths, additives, and storage and safety; insulin therapy (conventional and intensive); delivery of insulin (insulin shots and insulin pump); self monitoring of blood glucose, site rotation of injections, timing of injections, and blood glucose levels; syringe reuse; and syringe disposal. Insulin is classified according to how soon it starts working (onset), when it works the hardest (peak time), and how long it lasts in the body (duration). (AA-M).

•

Insulin: Helping Me Stay Healthy Source: Lexington, KY: Lexington-Fayette County Health Department. 199x. 13 p. Contact: Available from Lexington-Fayette County Health Department. Division of Nutrition and Health Education, 650 Newtown Pike, Lexington, KY 40508. (606) 2882333. Fax (606) 288-2359. PRICE: $38.00 per 25 copies plus shipping. Summary: This guide to insulin use is one in a series of 22 diabetes education materials that combine practical tips and humorous drawings with current diabetes information. The series is written at a sixth grade reading level and is designed to teach and motivate patients to take care of themselves. The booklet provides specific suggestions for readers to implement in their everyday diabetes management. The authors first describe how insulin is used in the body and the importance of combining insulin therapy with a healthy meal plan and a regular exercise plan. Topics in the remainder of the booklet include where insulin comes from, the types of insulin, when and how to take insulin, guidelines for the storage and care of insulin, drawing up and injecting insulin, and where to give insulin shots. The guidelines for drawing up and injecting insulin are provided in step-by-step fashion, with a line drawing illustrating each step. The booklet

Patient Resources

375

encourages readers to work closely with their diabetes educator to learn the proper way to use insulin. •

Managing Your Diabetes Without Insulin Source: Boston, MA: Joslin Diabetes Center. 1997. 33 p. Contact: Available from Joslin Publications, One Joslin Place, Boston, MA 02215. (800) 344-4501. Fax (617) 732-2562. PRICE: $32.50 for package of 10. ISBN: 1879091143. Summary: This illustrated booklet, written for people who have noninsulin-dependent diabetes mellitus (NIDDM), presents guidelines for managing diabetes without the use of insulin. The booklet explains that the key management goal with NIDDM is to learn lifestyle skills that will keep blood sugar levels within a healthful range. Actions that make this goal possible include eating properly, exercising regularly, and maintaining a healthy weight. The booklet discusses nutrition and offers basic eating guidelines, including practical tips for low-fat cooking and detecting high-fat foods when eating out. Exercise and weight-management guidelines, how and why to test blood sugar, medication, record keeping, foot care, traveling, and sick days are also discussed. The booklet details what can happen when diabetes is not properly managed and gives practical tips for changing behavior, setting goals, and keeping life balanced.

•

Injecting Insulin Source: South Deerfield, MA: Channing L. Bete Co., Inc. 1999. 2 p. Contact: Available from Channing L. Bete, Co., Inc. 200 State Road, South Deerfield, MA 01373-0200. (800) 628-7733. Fax (800) 499-6464. PRICE: $14.90 each; plus shipping and handling; quantity discounts available. Order number 97334A-06-99. Summary: This illustrated fact sheet focuses on the proper technique for injecting an unmixed dose of insulin. People who have diabetes may need to learn how to inject themselves with insulin. Steps involved in injecting insulin include gathering the necessary equipment, checking the insulin expiration date, washing one's hands, choosing an injection site, preparing the dose, filling the syringe, checking the syringe for air bubbles, injecting oneself, withdrawing the needle, and disposing of the used needle safely. The fact sheet provides insulin injection and storage tips.

•

Noninsulin-Dependent Diabetes Source: Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. 1992. 37 p. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Single copy free; bulk copies available. Summary: This illustrated guide for people with noninsulin-dependent diabetes (NIDDM) provides basic information about NIDDM and its management. Subjects discussed include a general overview of NIDDM, symptoms, causes, risk-factors, diagnosis, treatment, diabetes diet, alcoholic beverages, exercise, oral medications, insulin, monitoring of glucose levels, diabetes complications, special situations, dealing with diabetes, finding help, printed information, and resources on diabetes. 'Points to Remember' are highlighted throughout each section. The back cover features a detachable diabetes medical identification card.

376 Insulin

•

My Insulin Plan Source: Minneapolis, MN: International Diabetes Center. 1998. 4 p. Contact: Available from Park Nicollet Health Source. 3800 Park Nicollet Boulevard, Minneapolis, MN 55416. (800) 372-7776 or (612) 993-3534. Fax (612) 993-1840. PRICE: $1.25 each for 10-49 copies; $1.12 each for 50-99 copies; $1.03 each for 100-499 copies. ISBN: 1885115482. Summary: This pamphlet provides information about insulin administration for people who have diabetes. Topics include types of insulin, when to take insulin, why and when to inject insulin, insulin regimens, insulin storage, syringe disposal, hypoglycemia (low blood glucose), and hyperglycemia (high blood glucose). Because it absorbs insulin quickly and consistently, the abdomen (stomach area) is the best site for insulin injections. Insulin should not be injected in an area that will be affected by strenuous physical activity. Muscle activity causes insulin to be absorbed more readily and may cause blood glucose to drop too low. The brochure also includes space for a personal insulin plan. A sidebar provides insulin tips. (AA-M).

•

Mixing Insulins. Mezcla de Insulinas Source: Franklin Lakes, NJ: Becton Dickinson. 1993. 14 p. Contact: Available from Becton Dickinson and Company. Consumer Products Division, One Becton Drive, Franklin Lakes, NJ 07417-1883. (800) 526-4650 or (201) 847-7100. PRICE: Free. Summary: This pamphlet uses color photographs to demonstrate a technique for fillin a syringe with a mixed dose of two types of insulin. Proper disposal of syringes is also explained. The text is bilingual Spanish/English.

•

How Well Are Your Kidneys?: An Important Question for People with Type I Insulin-Dependent Diabetes Source: Princeton, NJ: Bristol-Myers Squibb Company. 1994. 17 p. Contact: Available from Becton-Dickinson Consumer Products. 1 Becton Drive, Franlin Lakes, NJ 07417. (800) 237-4554. PRICE: Single copy free. Summary: This patient education booklet is designed to help people with diabetes mellitus learn about diabetes-related kidney damage. The booklet also discusses CAPOTEN (captopril), a prescription drug treatment for many people with diabetic nephropathy. The booklet helps readers understand why their kidneys are so important, how insulin dependent diabetes can affect the kidneys; and what CAPOTEN can do to help if they are damaged by diabetes. Topics include the healthy kidney; the unhealthy kidney; the cause and incidence of kidney problems; symptoms of kidney disease; taking good care of the kidneys; the indications for CAPOTEN; and side effects of the drug. The latter half of the booklet consists of the insert information for CAPOTEN tablets.

•

Injecting 2 Kinds of Insulin Source: Atlanta, GA: Pritchett and Hull Associates, Inc. 1995. 4 p. Contact: Available from Pritchett and Hull Associates, Inc. 3440 Oakcliff Road NE., Suite 110, Atlanta, GA 30340-3079. (800) 241-4925 or (404) 451-0602. Fax (800) 752-0510 or (404) 454-7130. PRICE: $10 per pack of 50. Item Number 223.

Patient Resources

377

Summary: This patient education brochure explains to readers how to mix and inject two kinds of insulin. Written in clear, easy-to-understand language, the brochure takes readers step-by-step through preparing the insulin and the syringe. A second section shows the five steps necessary to inject insulin. Simple line drawings illustrate each step. Blank space for patient notes is also included. •

Record Book: Insulin, Insulin Pump Source: Minneapolis, MN: International Diabetes Center, Park Nicollet Medical Foundation. 1995. (record-keeping booklet). Contact: Available from HealthSource. 3800 Park Nicollet Boulevard, Minneapolis, MN 55416-9963. (800) 372-7776. PRICE: $1.95; discounts available for 10 or more copies. Summary: This record-keeping booklet provides blank charts on which people can record their blood glucose levels, insulin intake, and ketones; space for notes and comments is also provided. The booklet includes charts for 26 weeks' worth of records.

•

Rhonda Learns About Insulin Source: Philadelphia, PA: Health Promotion Council of Southeastern Pennsylvania. 199x. 2 p. Contact: Available from Health Promotion Council of Southeastern Pennsylvania. 260 S. Broad Street, Philadelphia, PA 19102. (215) 731-6150. Website: www.hpcpa.org. PRICE: Single copy free for sample pamphlets; contact Health Promotion Council of Southeastern Pennsylvania for master copy prices. Summary: This simple brochure teaches the reader the basic facts of diabetes mellitus and how it is treated with insulin. Through a brief narrative of one woman's early education about diabetes, the brochure discusses how insulin helps the body to utilize food, what happens when one's body doesn't make enough insulin, who can use oral medication instead of insulin, the role of exercise and good nutrition, and the importance of patient education and working closely with health professionals to achieve the best diabetes control possible. Simple line drawings illustrate the concepts presented.

•

Taking Your Insulin Source: San Bruno, CA: Krames Communications. 1997. 2 p. Contact: Available from Krames Communications. 1100 Grundy Lane, San Bruno, CA 94066-3030. (800) 333-3032. Fax (415) 244-4512. PRICE: $12.50 for pad of 50 sheets. Summary: This two-sided handout provides people who have diabetes with information about injecting insulin. Topics include where to place injections, how to inject insulin, and storing insulin. The fact sheet notes that insulin is most often injected into the abdomen. In order to prevent skin problems, people should change injection sites each time and allow about one inch between sites. Insulin should never be frozen or allowed to get too hot. The fact sheet suggests that it be stored in the door of the refrigerator. The fact sheet is written in nontechnical language and includes color pictures relevant to each of the sections. An area for recording special instructions is provided at the end of the fact sheet. (AA-M).

378 Insulin

Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

A Child With Diabetes is in Your Care: Facts You'll Need to Know Summary: Information for people who may be responsible for a child with diabetes. This fact sheet provides basic information about Type 1 (insulin-dependent or juvenile) diabetes. Source: Juvenile Diabetes Research Foundation International http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6259

•

All About Insulin Summary: This online consumer fact sheet discusses diabetic insulin therapy. Includes information on usage, storage and safety, and syringe re-use and disposal. Source: American Diabetes Association http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2219

•

Do You Know What Diabetes Is? Summary: This fact sheet discusses diabetes -- particularly insulin-dependent diabetes -and its affect on the daily life of children and adolescents affected by the disorder. Source: Nemours Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5531

•

FDA Diabetes Information Summary: This site links to information on glucose meters and diabetes management, food and meal planning, insulin, diabetes pills, lancing devices and sharps disposal, and complications of diabetes. Source: Center for Devices and Radiological Health, U.S. Food and Drug Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6922

•

Helpful Hints in the Use of Insulin Summary: This mini-fact sheet provides answers to diabetic patients' questions regarding the correct use of insulin -- includes information on insulin storage and the reuse and disposal of syringes. Source: Joslin Diabetes Center http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2220

Patient Resources

•

379

The Pima Indians: Pathfinders for Health Summary: By studying Pima Indian volunteers, researchers have determined that diabetes runs in families, as does insulin resistance, and obesity. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2624

•

Treating Insulin Reactions Summary: Answers to questions about insulin reactions -- symptoms (shakiness, dizziness, sweating, hunger, headache, or sudden mood changes) and treatment. Source: American Diabetes Association http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2218 The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to insulin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to insulin. By consulting all of associations listed in this

380 Insulin

chapter, you will have nearly exhausted all sources for patient associations concerned with insulin. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about insulin. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “insulin” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “insulin”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “insulin” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “insulin” (or a synonym) into the search box, and click “Submit Query.”

Patient Resources

381

383

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.27

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

27

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

384 Insulin

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)28: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

28

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

385

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

386 Insulin

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

387

•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

388 Insulin

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

389

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on insulin: •

Basic Guidelines for Insulin Insulin C-peptide Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003701.htm Insulin test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003700.htm Insulinoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000387.htm

•

Signs & Symptoms for Insulin Anxiety Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm

390 Insulin

Convulsions Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm Decreased consciousness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Dizziness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003093.htm Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Hunger Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003134.htm Loss of consciousness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Muscle Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Obesity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003101.htm Rapid heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Sweating Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003218.htm •

Diagnostics and Tests for Insulin Blood glucose Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003482.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Triglycerides Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003493.htm Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm

•

Nutrition for Insulin Proteins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm

Online Glossaries 391

•

Background Topics for Insulin Adolescent test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002054.htm Benign Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002236.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Distal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002346.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm Metastasis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002260.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Schoolage test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002058.htm Toddler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002056.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

393

INSULIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetohexamide: A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1hydrohexamide. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing

394 Insulin

of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adenylate Kinase: An enzyme that catalyzes the phosphorylation of AMP to ADP in the presence of ATP or inorganic triphosphate. EC 2.7.4.3. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal insufficiency: The reduced secretion of adrenal glands. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenaline: A hormone. Also called epinephrine. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH]

Dictionary 395

Adult-Onset Diabetes: Former term for noninsulin-dependent or type II diabetes. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure

396 Insulin

and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldose Reductase Inhibitor: A class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Aldose reductase is an enzyme that is normally present in the eye and in many other parts of the body. It helps change glucose (sugar) into a sugar alcohol called sorbitol. Too much sorbitol trapped in eye and nerve cells can damage these cells, leading to retinopathy and neuropathy. Drugs that prevent or slow (inhibit) the action of aldose reductase are being studied as a way to prevent or delay these complications of diabetes. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha Cell: A type of cell in the pancreas (in areas called the islets of Langerhans). Alpha cells make and release a hormone called glucagon, which raises the level of glucose (sugar) in the blood. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon

Dictionary 397

may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylactic: Pertaining to anaphylaxis. [EU] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory

398 Insulin

distress, vascular collapse, systemic shock, and death. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory

Dictionary 399

and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Anthropometric measurements: Measurements of human body height, weight, and size of component parts, including skinfold measurement. Used to study and compare the relative proportions under normal and abnormal conditions. [NIH] Anthropometry: The technique that deals with the measurement of the size, weight, and proportions of the human or other primate body. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibodies, Anticardiolipin: Antiphospholipid antibodies found in association with systemic lupus erythematosus (lupus erythematosus, systemic), antiphospholipid syndrome, and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. [NIH] Antibodies, Antiphospholipid: Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome, related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antidiabetic Agent: A substance that helps a person with diabetes control the level of glucose (sugar) in the blood so that the body works as it should. [NIH] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue

400 Insulin

cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiphospholipid Syndrome: The presence of antibodies directed against phospholipids (antibodies, antiphospholipid). The condition is associated with a variety of diseases, notably systemic lupus erythematosus and other connective tissue diseases, thrombopenia, and arterial or venous thromboses. In pregnancy it can cause abortion. Of the phospholipids, the cardiolipins show markedly elevated levels of anticardiolipin antibodies (antibodies, anticardiolipin). Present also are high levels of lupus anticoagulant (lupus coagulation inhibitor). [NIH] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Antrectomy: An operation to remove the upper portion of the stomach, called the antrum. This operation helps reduce the amount of stomach acid. It is used when a person has complications from ulcers. [NIH] Anuria: Inability to form or excrete urine. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH]

Dictionary 401

Apnoea: Cessation of breathing. [EU] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arcuate Nucleus: A nucleus located in the middle hypothalamus in the most ventral part of the third ventricle near the entrance of the infundibular recess. Its small cells are in close contact with the ependyma. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriography: A procedure to x-ray arteries. The arteries can be seen because of an injection of a dye that outlines the vessels on an x-ray. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of

402 Insulin

the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Articular: Of or pertaining to a joint. [EU] Artificial Pancreas: A large machine used in hospitals that constantly measures glucose (sugar) in the blood and, in response, releases the right amount of insulin. Scientists are also working to develop a small unit that could be implanted in the body, functioning like a real pancreas. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to

Dictionary 403

strains of unusual type. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autosuggestion: Suggestion coming from the subject himself. [NIH] Avidin: A specific protein in egg albumin that interacts with biotin to render it unavailable to mammals, thereby producing biotin deficiency. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus

404 Insulin

and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Belladonna: A species of very poisonous Solanaceous plants yielding atropine (hyoscyamine), scopolamine, and other belladonna alkaloids, used to block the muscarinic autonomic nervous system. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Biliopancreatic Diversion: A surgical procedure which diverts pancreatobiliary secretions via the duodenum and the jejunum into the colon, the remaining small intestine being anastomosed to the stomach after antrectomy. The procedure produces less diarrhea than does jejunoileal bypass. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [NIH] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH]

Dictionary 405

Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomass: Total mass of all the organisms of a given type and/or in a given area. (From Concise Dictionary of Biology, 1990) It includes the yield of vegetative mass produced from any given crop. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH]

406 Insulin

Blood-Retinal Barrier: Specialized nonfenestrated tightly-joined endothelial cells that form a transport barrier for certain substances between the retinal capillaries and the retinal tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bolus injection: The injection of a drug (or drugs) in a high quantity (called a bolus) at once, the opposite of gradual administration (as in intravenous infusion). [EU] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the

Dictionary 407

respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buformin: An oral hypoglycemic agent that inhibits gluconeogenesis, increases glycolysis, and decreases glucose oxidation. [NIH] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Bullous: Pertaining to or characterized by bullae. [EU] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH]

408 Insulin

Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Captopril: A potent and specific inhibitor of peptidyl-dipeptidase A. It blocks the conversion of angiotensin I to angiotensin II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the renin-angiotensin system and inhibits pressure responses to exogenous angiotensin. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiotoxicity: Toxicity that affects the heart. [NIH]

Dictionary 409

Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Cathepsins: A group of lysosomal proteinases or endopeptidases found in aqueous extracts of a variety of animal tissue. They function optimally within an acidic pH range. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins

410 Insulin

have been identified. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH]

Dictionary 411

Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Aqueduct: Narrow channel in the mesencephalon that connects the third and fourth ventricles. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH] Chlorpromazine: The prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine's antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup. [NIH] Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions. Cholecystokinin may be the mediator of satiety. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Choleretic: A choleretic agent. [EU] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla.

412 Insulin

[NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of

Dictionary 413

certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Claudication: Limping or lameness. [EU] Claviceps: A genus of ascomycetous fungi, family Clavicipitaceae, order Hypocreales, parasitic on various grasses. The sclerotia contain several toxic alkaloids. Claviceps purpurea on rye causes ergotism. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clozapine: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a

414 Insulin

water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Colostrum: The thin, yellow, serous fluid secreted by the mammary glands during pregnancy and immediately postpartum before lactation begins. It consists of immunologically active substances, white blood cells, water, protein, fat, and carbohydrates. [NIH]

Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Competency: The capacity of the bacterium to take up DNA from its surroundings. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a

Dictionary 415

bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH]

416 Insulin

Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraceptive Agents: Chemical substances that prevent or reduce the probability of conception. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of

Dictionary 417

formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Corticotropin-Releasing Hormone: A neuropeptide released by the hypothalamus that stimulates the release of corticotropin by the anterior pituitary gland. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Coumarin: A fluorescent dye. [NIH] Coumestrol: A coumarin derivative occurring naturally in forage crops which has

418 Insulin

estrogenic activity. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH] Cyproterone Acetate: An agent with anti-androgen and progestational properties. It shows competitive binding with dihydrotestosterone at androgen receptor sites. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior

Dictionary 419

of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]

Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive

420 Insulin

stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermatitis: Any inflammation of the skin. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desogestrel: A synthetic progestational hormone used often as the progestogenic component of combined oral contraceptive agents. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] DHEA: Dehydroepiandrosterone. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the

Dictionary 421

background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]

Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or

422 Insulin

more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease Vectors: Invertebrates or non-human vertebrates which transmit infective organisms from one host to another. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dispenser: Glass, metal or plastic shell fitted with valve from which a pressurized formulation is dispensed; an instrument for atomizing. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulphide: A covalent bridge formed by the oxidation of two cysteine residues to a cystine residue. The-S-S-bond is very strong and its presence confers additional stability. [NIH] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diurnal: Occurring during the day. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a

Dictionary 423

delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Doxazosin: A selective alpha-1-adrenergic blocker that lowers serum cholesterol. It is also effective in the treatment of hypertension. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Utilization: The utilization of drugs as reported in individual hospital studies, FDA studies, marketing, or consumption, etc. This includes drug stockpiling, and patient drug profiles. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dynein: A transport protein that normally binds proteins to the microtubule. [NIH] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH]

424 Insulin

Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH]

Dictionary 425

Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH]

426 Insulin

End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Ependyma: A thin membrane that lines the ventricles of the brain and the central canal of the spinal cord. [NIH] Ependymal: It lines the cavities of the brain's ventricles and the spinal cord and slowly divides to create a stem cell. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic

Dictionary 427

vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]

Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethanolamine: A viscous, hygroscopic amino alcohol with an ammoniacal odor. It is widely

428 Insulin

distributed in biological tissue and is a component of lecithin. It is used as a surfactant, fluorimetric reagent, and to remove CO2 and H2S from natural gas and other gases. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exemestane: An anticancer drug used to decrease estrogen production and suppress the growth of estrogen-dependent tumors. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by a single case report or a limited number of patients. This should be differentiated from death, the physiological cessation of life and from mortality, an epidemiological or statistical

Dictionary 429

concept. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Ferrets: Semidomesticated variety of European polecat much used for hunting rodents and/or rabbits and as a laboratory animal. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so

430 Insulin

that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Food Habits: Acquired or learned food preferences. [NIH] Food Preferences: The selection of one food over another. [NIH] Food Technology: The application of knowledge to the food industry. [NIH] Foot Care: Taking special steps to avoid foot problems such as sores, cuts, bunions, and calluses. Good care includes daily examination of the feet, toes, and toenails and choosing shoes and socks or stockings that fit well. People with diabetes have to take special care of their feet because nerve damage and reduced blood flow sometimes mean they will have less feeling in their feet than normal. They may not notice cuts and other problems as soon as they should. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the

Dictionary 431

gallbladder or bile ducts. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglioside: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]

Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase

432 Insulin

arrest in human and murine cell lines. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Gliclazide: An oral sulfonylurea hypoglycemic agent which stimulates insulin secretion. [NIH]

Glipizide: An oral hypoglycemic agent which is rapidly absorbed and completely metabolized. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH]

Dictionary 433

Glucose Clamp Technique: Maintenance of a constant blood glucose level by perfusion or infusion with glucose or insulin. It is used for the study of metabolic rates (e.g., in glucose, lipid, amino acid metabolism) at constant glucose concentration. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 3.1.3.9. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glyburide: An antidiabetic sulfonylurea derivative with actions similar to those of chlorpropamide. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH]

434 Insulin

Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosuria: The presence of glucose in the urine; especially the excretion of an abnormally large amount of sugar (glucose) in the urine, i.e., more than 1 gm. in 24 hours. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH]

Dictionary 435

Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH]

436 Insulin

Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatoma: A liver tumor. [NIH] Herbicides: Pesticides used to destroy unwanted vegetation, especially various types of weeds, grasses, and woody plants. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring.

Dictionary 437

2. The genetic constitution of an individual. [EU] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hiccup: A spasm of the diaphragm that causes a sudden inhalation followed by rapid closure of the glottis which produces a sound. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]

Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydatidiform Mole: A trophoblastic disease characterized by hydrops of the mesenchymal portion of the villus. Its karyotype is paternal and usually homozygotic. The tumor is indistinguishable from chorioadenoma destruens or invasive mole ( = hydatidiform mole, invasive) except by karyotype. There is no apparent relation by karyotype to choriocarcinoma. Hydatidiform refers to the presence of the hydropic state of some or all of the villi (Greek hydatis, a drop of water). [NIH]

438 Insulin

Hydrochlorothiazide: A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [NIH] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperammonemia: Metabolic disorder characterized by elevated level of ammonia in blood. [NIH] Hyperandrogenism: A state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. It is often caused by ovarian disease (particularly the polycystic ovary syndrome) and by adrenal diseases (particularly adrenal gland hyperfunction). [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycaemia: Abnormally increased content of sugar in the blood. [EU] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor

Dictionary 439

formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypodermic: Applied or administered beneath the skin. [EU] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypophyseal: Hypophysial. [EU] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hysteria: Historical term for a chronic, but fluctuating, disorder beginning in early life and characterized by recurrent and multiple somatic complaints not apparently due to physical illness. This diagnosis is not used in contemporary practice. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders

440 Insulin

induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ice Cream: A frozen dairy food made from cream or butterfat, milk, sugar, and flavorings. Frozen custard and French-type ice creams also contain eggs. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to

Dictionary 441

prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infuse: To pour (a liquid) into something. [EU] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH]

442 Insulin

Infusion Pumps: Fluid propulsion systems driven mechanically, electrically, or osmotically that are used to inject (or infuse) over time agents into a patient or experimental animal; used routinely in hospitals to maintain a patent intravenous line, to administer antineoplastic agents and other drugs in thromboembolism, heart disease, diabetes mellitus (insulin infusion systems is also available), and other disorders. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inositol 1,4,5-Trisphosphate: Intracellular messenger formed by the action of phospholipase C on phosphatidylinositol 4,5-bisphosphate, which is one of the phospholipids that make up the cell membrane. Inositol 1,4,5-trisphosphate is released into the cytoplasm where it releases calcium ions from internal stores within the cell's endoplasmic reticulum. These calcium ions stimulate the activity of B kinase or calmodulin. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin Infusion Systems: Portable or implantable devices for infusion of insulin. Includes open-loop systems which may be patient-operated or controlled by a pre-set program and are designed for constant delivery of small quantities of insulin, increased during food ingestion, and closed-loop systems which deliver quantities of insulin automatically based on an electronic glucose sensor. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Insulin-Like Growth Factor-Binding Protein 2: One of the six homologous soluble proteins that bind insulin-like growth factors (somatomedins) and modulate their mitogenic and metabolic actions at the cellular level. [NIH]

Dictionary 443

Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

444 Insulin

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Isotonic: A biological term denoting a solution in which body cells can be bathed without a net flow of water across the semipermeable cell membrane. Also, denoting a solution having the same tonicity as some other solution with which it is compared, such as physiologic salt solution and the blood serum. [EU] Isozymes: The multiple forms of a single enzyme. [NIH] Jejunoileal Bypass: A surgical procedure consisting of the anastomosis of the proximal part of the jejunum to the distal portion of the ileum, so as to bypass the nutrient-absorptive segment of the small intestine, to treat morbid obesity. [NIH] Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can

Dictionary 445

also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketonuria: Having ketone bodies in the urine; a warning sign of diabetic ketoacidosis (DKA). [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] Laparoscopy: Examination, therapy or surgery of the abdomen's interior by means of a laparoscope. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larva: Wormlike or grublike stage, following the egg in the life cycle of insects, worms, and other metamorphosing animals. [NIH] Laryngoscopy: Examination, therapy, or surgery of the interior of the larynx performed with a specially designed endoscope. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no

446 Insulin

troublesome effect. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH]

Dictionary 447

Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH]

448 Insulin

Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lyssavirus: A genus of the family Rhabdoviridae that includes rabies virus and other rabieslike viruses. [NIH]

Dictionary 449

Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH]

450 Insulin

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megestrol: 17-Hydroxy-6-methylpregna-3,6-diene-3,20-dione. A progestational hormone used most commonly as the acetate ester. As the acetate, it is more potent than progesterone both as a progestagen and as an ovulation inhibitor. It has also been used in the palliative treatment of breast cancer. [NIH] Megestrol Acetate: A drug that belongs to the group of hormones called progestins, used as hormone therapy to block estrogen and to suppress the effects of estrogen and androgens. [NIH]

Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH]

Dictionary 451

Menthol: An alcohol produced from mint oils or prepared synthetically. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Metamorphosis: The ontogeny of insects, i. e. the series of changes undergone from egg, through larva and pupa, or through nymph, to adult. [NIH] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH]

452 Insulin

Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Midaxillary line: An imaginary vertical line that passes midway between the anterior and posterior axillary (armpit) folds. [NIH] Mifepristone: A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary Cushing syndrome. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Millimeter: A measure of length. A millimeter is approximately 26-times smaller than an inch. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH]

Dictionary 453

Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monounsaturated fat: An unsaturated fat that is found primarily in plant foods, including olive and canola oils. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result

454 Insulin

in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH]

Dictionary 455

Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system.

456 Insulin

[NIH]

Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutralization: An act or process of neutralizing. [EU] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nonblinded: Describes a clinical trial or other experiment in which the researchers know what treatments are being given to each study subject or experimental group. If human subjects are involved, they know what treatments they are receiving. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by

Dictionary 457

polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritive Value: An indication of the contribution of a food to the nutrient content of the diet. This value depends on the quantity of a food which is digested and absorbed and the amounts of the essential nutrients (protein, fat, carbohydrate, minerals, vitamins) which it contains. This value can be affected by soil and growing conditions, handling and storage, and processing. [NIH] Nymph: The immature stage in the life cycle of those orders of insects characterized by gradual metamorphosis, in which the young resemble the imago in general form of body, including compound eyes and external wings; also the 8-legged stage of mites and ticks that follows the first moult. [NIH] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oleic Acids: A group of fatty acids that contain 16 carbon atoms and a double bond at the omega 9 carbon. [NIH] Oligo: Chemical and mineral elements that exist in minimal (oligo) quantities in the body, in foods, in the air, in soil; name applied to any element observed as a microconstituent of plant or animal tissue and of beneficial, harmful, or even doubtful significance. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH]

458 Insulin

Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Organoleptic: Of, relating to, or involving the employment of the sense organs; used especially of subjective testing (as of flavor, odor, appearance) of food and drug products. [NIH]

Orlistat: A lipase inhibitor used for weight loss. Lipase is an enzyme found in the bowel that assists in lipid absorption by the body. Orlistat blocks this enzyme, reducing the amount of fat the body absorbs by about 30 percent. It is known colloquially as a "fat blocker." Because more oily fat is left in the bowel to be excreted, Orlistat can cause an oily anal leakage and fecal incontinence. Orlistat may not be suitable for people with bowel conditions such as irritable bowel syndrome or Crohn's disease. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH]

Dictionary 459

Ouabain: A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging atpase. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreas Transplant: A surgical procedure that involves replacing the pancreas of a person who has diabetes with a healthy pancreas that can make insulin. The healthy pancreas

460 Insulin

comes from a donor who has just died or from a living relative. A person can donate half a pancreas and still live normally. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Hormones: Peptide hormones secreted into the blood by cells in the Islets of Langerhans of the pancreas. The alpha cells secrete glucagon; the beta cells secrete insulin; the delta cells secrete somatostatin; and the PP cells secrete pancreatic polypeptide. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatic Polypeptide: A 36-amino acid polypeptide with physiological regulatory functions. It is secreted by pancreatic tissue. Plasma pancreatic polypeptide increases after ingestion of food, with age, and in disease states. A lack of pancreatic polypeptide in the islets of Langerhans has been associated with the obese syndrome in rats and mice. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural

Dictionary 461

and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Perineal: Pertaining to the perineum. [EU] Perineum: The area between the anus and the sex organs. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the

462 Insulin

greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phlebotomy: The letting of blood from a vein. Although it is one of the techniques used in drawing blood to be used in diagnostic procedures, in modern medicine, it is used commonly in the treatment of erythrocytosis, hemochromocytosis, polycythemia vera, and porphyria cutanea tarda. Its historical counterpart is bloodletting. (From Cecil Textbook of Medicine, 19th ed & Wintrobe's Clinical Hematology, 9th ed) Venipuncture is not only for the letting of blood from a vein but also for the injecting of a drug into the vein for

Dictionary 463

diagnostic analysis. [NIH] Phobia: A persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. When a phobia is a significant source of distress or interferes with social functioning, it is considered a mental disorder; phobic disorder (or neurosis). In DSM III phobic disorders are subclassified as agoraphobia, social phobias, and simple phobias. Used as a word termination denoting irrational fear of or aversion to the subject indicated by the stem to which it is affixed. [EU] Phobic Disorders: Anxiety disorders in which the essential feature is persistent and irrational fear of a specific object, activity, or situation that the individual feels compelled to avoid. The individual recognizes the fear as excessive or unreasonable. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their

464 Insulin

cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Piloerection: Involuntary erection or bristling of hairs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Placental tissue: The tissue intervening between fetal blood and maternal blood in the placenta; it acts as a selective membrane regulating the passage of substances from the maternal to the fetal blood. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain

Dictionary 465

pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Plethysmography: Recording of change in the size of a part as modified by the circulation in it. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU]

466 Insulin

Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Port: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port-a-cath. [NIH] Port-a-cath: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port. [NIH] Post partum: After childbirth, or after delivery. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of

Dictionary 467

the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Pre-Eclampsia: Development of hypertension with proteinuria, edema, or both, due to pregnancy or the influence of a recent pregnancy. It occurs after the 20th week of gestation, but it may develop before this time in the presence of trophoblastic disease. [NIH] Pre-eclamptic: A syndrome characterized by hypertension, albuminuria, and generalized oedema, occurring only in pregnancy. [NIH] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH]

468 Insulin

Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Pro-Opiomelanocortin: A precursor protein, MW 30,000, synthesized mainly in the anterior pituitary gland but also found in the hypothalamus, brain, and several peripheral tissues. It incorporates the amino acid sequences of ACTH and beta-lipotropin. These two hormones, in turn, contain the biologically active peptides MSH, corticotropin-like intermediate lobe peptide, alpha-lipotropin, endorphins, and methionine enkephalin. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the

Dictionary 469

prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not

470 Insulin

working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]

Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psyllium: Dried, ripe seeds of Plantago psyllium, P. indica, and P. ovata (Plantaginaceae). Plantain seeds swell in water and are used as demulcents and bulk laxatives. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupa: An inactive stage between the larval and adult stages in the life cycle of insects. [NIH]

Dictionary 471

Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Rabies: A highly fatal viral infection of the nervous system which affects all warm-blooded animal species. It is one of the most important of the zoonoses because of the inevitably fatal outcome for the infected human. [NIH] Rabies Virus: The type species of lyssavirus causing rabies in humans and other animals. Transmission is mostly by animal bites through saliva. The virus is neurotropic multiplying in neurons and myotubes of vertebrates. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH]

472 Insulin

Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Relaxin: Hormone produced by the ovaries during pregnancy that loosens ligaments that

Dictionary 473

hold the hip bones together. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Resting metabolic rate: RMR accounts for 65 to 75 percent of daily energy expenditure and represents the minimum energy needed to maintain all physiological cell functions in the resting state. The principal determinant of RMR is lean body mass (LBM). Obese subjects have a higher RMR in absolute terms than lean individuals, an equivalent RMR when corrected for LBM and per unit surface area, and a lower RMR when expressed per kilogram of body weight. Obese persons require more energy for any given activity because of a larger mass, but they tend to be more sedentary than lean subjects. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour

474 Insulin

vision. Called also retinal, and retinene1. [EU] Retinal Neovascularization: Formation of new blood vessels originating from the retinal veins and extending along the inner (vitreal) surface of the retina. [NIH] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [NIH]

Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rod Outer Segments: The portion of the retinal rod cell between the inner segment and the pigment epithelium layer of the retina. [NIH] Rodenticides: Substances used to destroy or inhibit the action of rats, mice, or other rodents. [NIH]

Dictionary 475

Rosiglitazone: A drug taken to help reduce the amount of sugar in the blood. Rosiglitazone helps make insulin more effective and improves regulation of blood sugar. It belongs to the family of drugs called thiazolidinediones. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Rye: A hardy grain crop, Secale cereale, grown in northern climates. It is the most frequent host to ergot (claviceps), the toxic fungus. Its hybrid with wheat is triticale, another grain. [NIH]

Salicylate: Non-steroidal anti-inflammatory drugs. [NIH] Salicylic: A tuberculosis drug. [NIH] Salicylic Acids: Derivatives and salts of salicylic acid. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Sampling Studies: Studies in which a number of subjects are selected from all subjects in a defined population. Conclusions based on sample results may be attributed only to the population sampled. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Satiation: Full gratification of a need or desire followed by a state of relative insensitivity to that particular need or desire. [NIH] Satiety Response: Behavioral response associated with the achieving of gratification. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to

476 Insulin

create pictures of areas inside the body. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senile Plaques: Spherical masses consisting of amyloid fibrils and neuronal processes. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU]

Dictionary 477

Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shivering: Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Sibutramine: A drug used for the management of obesity that helps reduce food intake and is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. It works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin. Side effects include dry mouth, headache, constipation, insomnia, and a slight increase in average blood pressure. In some

478 Insulin

patients it causes a higher blood pressure increase. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of

Dictionary 479

dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatomedins: Insulin-like polypeptides made by the liver and some fibroblasts and released into the blood when stimulated by somatotropin. They cause sulfate incorporation into collagen, RNA, and DNA synthesis, which are prerequisites to cell division and growth of the organism. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU]

480 Insulin

Squamous: Scaly, or platelike. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by

Dictionary 481

clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcommissural Organ: An ependymal derivative located at the junction of the third ventricle and the cerebral aqueduct, secreting somatostatin. [NIH] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sympathectomy: The removal or interruption of some part of the sympathetic nervous system for therapeutic or research purposes. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH]

482 Insulin

Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU]

Dictionary 483

Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermogenesis: The generation of heat in order to maintain body temperature. The uncoupled oxidation of fatty acids contained within brown adipose tissue and shivering are examples of thermogenesis in mammals. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thinness: A state of insufficient flesh on the body usually defined as having a body weight less than skeletal and physical standards. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombopenia: Reduction in the number of platelets in the blood. [NIH] Thromboses: The formation or presence of a blood clot within a blood vessel during life. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation.

484 Insulin

Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thylakoids: Membranous cisternae of the chloroplast containing photosynthetic pigments, reaction centers, and the electron-transport chain. Each thylakoid consists of a flattened sac of membrane enclosing a narrow intra-thylakoid space (Lackie and Dow, Dictionary of Cell Biology, 2nd ed). Individual thylakoids are interconnected and tend to stack to form aggregates called grana. They are found in cyanobacteria and all plants. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tissue Transplantation: Transference of tissue within an individual, between individuals of the same species, or between individuals of different species. [NIH] Tolazamide: A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU]

Dictionary 485

Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transport Vesicles: Vesicles that are involved in shuttling cargo from the interior of the cell to the cell surface, from the cell surface to the interior, across the cell or around the cell to various locations. [NIH]

486 Insulin

Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH]

Dictionary 487

Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ultralente Insulin: A type of insulin that is long acting. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unit of Insulin: The basic measure of insulin. U-100 insulin means 100 units of insulin per milliliter (mL) or cubic centimeter (cc) of solution. Most insulin made today in the United States is U-100. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urine Testing: Checking urine to see if it contains glucose (sugar) and ketones. Special strips of paper or tablets (called reagents) are put into a small amount of urine or urine plus water. Changes in the color of the strip show the amount of glucose or ketones in the urine. Urine testing is the only way to check for the presence of ketones, a sign of serious illness. However, urine testing is less desirable then blood testing for monitoring the level of glucose in the body. [NIH] Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation

488 Insulin

due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vanadium: Vanadium. A metallic element with the atomic symbol V, atomic number 23, and atomic weight 50.94. It is used in the manufacture of vanadium steel. Prolonged exposure can lead to chronic intoxication caused by absorption usually via the lungs. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives

Dictionary 489

oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinarians: Individuals with a degree in veterinary medicine that provides them with training and qualifications to treat diseases and injuries of animals. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vial: A small bottle. [EU] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virilism: Development of masculine traits in the female. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH]

490 Insulin

Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Waist circumference: To define the level at which the waist circumference is measured, a bony landmark is first located and marked. The subject stands, and the technician, positioned to the right of the subject, palpates the upper hip bone to locate the right ileum. Just above the uppermost lateral border of the right ileum, a horizontal mark is drawn and then crossed with a vertical mark on the midaxillary line. The measuring tape is then placed around the trunk, at the level of the mark on the right side, making sure that it is on a level horizontal plane on all sides. The tape is then tightened slightly without compressing the skin and underlying subcutaneous tissues. The measure is recorded in centimeters to the nearest millimeter. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight Lifting: A sport in which weights are lifted competitively or as an exercise. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zearalenone: (S-(E))-3,4,5,6,8,10-Hexahydro-14,16-dihydroxy-3-methyl-1H-2benzoxacyclotetradecin-1,7(8H)-dione. One of a group of compounds known under the general designation of resorcylic acid lactones. Cis, trans, dextro and levo forms have been isolated from the fungus Gibberella zeae (formerly Fusarium graminearum). They have estrogenic activity, cause toxicity in livestock as feed contaminant, and have been used as anabolic or estrogen substitutes. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

491

INDEX 1 1-phosphate, 78, 393, 463 A Abdomen, 4, 222, 223, 317, 376, 377, 393, 405, 406, 426, 443, 445, 447, 460, 461, 480, 483 Abdominal, 22, 47, 59, 223, 248, 323, 336, 374, 393, 394, 443, 444, 447, 459, 460, 461, 462, 489 Abdominal fat, 22, 47, 224, 336, 393, 489 Aberrant, 78, 240, 276, 393 Ablation, 42, 70, 393 Acanthosis Nigricans, 45, 77, 352, 393 Acceptor, 393, 447, 459, 485 Acetohexamide, 280, 393 Acetylcholine, 29, 184, 393, 412, 456 Acetylcysteine, 211, 393 Acetylgalactosamine, 393, 434 Acetylglucosamine, 393, 434 Acidosis, 393, 420 Acne, 71, 393, 418 Actin, 65, 82, 181, 208, 393, 454, 455 Acyl, 62, 90, 393, 427 Adaptability, 393, 410 Adaptation, 23, 59, 143, 393, 411, 464 Adenine, 98, 394, 471 Adenocarcinoma, 394, 436 Adenosine, 99, 119, 205, 394, 402, 407, 439, 463 Adenosine Monophosphate, 119, 394 Adenovirus, 33, 63, 82, 394 Adenylate Cyclase, 84, 159, 163, 394, 411 Adenylate Kinase, 278, 394 Adipose Tissue, 28, 35, 40, 53, 59, 71, 73, 78, 85, 110, 111, 140, 229, 235, 241, 248, 251, 270, 276, 303, 323, 393, 394, 447, 483 Adjustment, 4, 13, 15, 107, 303, 313, 321, 325, 369, 393, 394 Adjuvant, 34, 174, 394, 431 Adolescence, 38, 394 Adrenal Cortex, 394, 396, 417, 427, 438, 467, 473 Adrenal Glands, 394 Adrenal insufficiency, 120, 152, 394 Adrenal Medulla, 394, 426, 456 Adrenaline, 312, 394 Adrenergic, 80, 100, 107, 110, 122, 191, 394, 400, 422, 423, 426, 481

Adsorption, 291, 394 Adsorptive, 394 Adult-Onset Diabetes, 274, 395 Adverse Effect, 28, 32, 284, 395, 413, 478 Aerobic, 12, 27, 30, 64, 216, 230, 395, 452, 459 Aerobic Exercise, 27, 30, 64, 395 Aerobic Metabolism, 395, 459 Aerobic Respiration, 395, 459 Aerosol, 20, 395, 481 Afferent, 395, 446 Affinity, 28, 65, 83, 116, 279, 395, 413, 447, 451, 478 Agar, 395, 418, 464 Age of Onset, 395, 486 Ageing, 247, 395 Agonist, 29, 51, 243, 272, 279, 395, 422, 456, 471, 482 Agoraphobia, 395, 463 Airway, 395, 407, 478 Albumin, 258, 395, 403, 464 Aldehydes, 396, 490 Aldose Reductase Inhibitor, 236, 396 Aldosterone, 55, 121, 396 Alertness, 396, 407 Alfalfa, 191, 267, 396 Algorithms, 396, 405 Alimentary, 396, 421, 426, 444, 460 Alkaline, 393, 396, 397, 407, 462, 482 Alkaloid, 396, 402, 456 Alleles, 70, 396 Allergen, 396, 420, 476 Allogeneic, 220, 258, 396, 434 Allograft, 90, 220, 396 Alpha Cell, 396, 460 Alpha-1, 396, 423, 463 Alternative medicine, 334, 396 Alternative Splicing, 49, 126, 396, 469 Ameliorating, 59, 397 Amenorrhea, 397, 399, 465 Amino Acid Sequence, 95, 248, 251, 397, 398, 399, 428, 431, 468, 477 Ammonia, 397, 433, 438, 481, 487 Amniotic Fluid, 397, 432 Amplification, 153, 158, 162, 285, 290, 397 Ampulla, 397, 411 Amputation, 38, 210, 237, 397 Amylase, 266, 397

492 Insulin

Amyloid, 91, 94, 106, 269, 333, 397, 476 Anabolic, 60, 63, 65, 78, 243, 279, 295, 397, 421, 490 Anaerobic, 121, 397 Anaesthesia, 146, 184, 397, 441 Anal, 397, 429, 458 Analgesic, 397, 446 Analog, 10, 13, 16, 54, 81, 109, 259, 264, 316, 397, 444, 457 Analogous, 22, 397, 485 Analytes, 294, 358, 359, 397 Anaphylactic, 397, 465 Anaphylaxis, 83, 397 Anatomical, 398, 402, 421, 424, 441, 476 Androgen-Binding Protein, 398, 477 Androgens, 41, 71, 394, 398, 401, 417, 438, 450 Anemia, 355, 398, 430, 449, 471 Anesthetics, 398, 427 Aneurysm, 398, 488 Angina, 13, 216, 398 Angiogenesis, 145, 398 Angiopathy, 250, 262, 398 Angioplasty, 123, 127, 216, 398, 454 Angiotensin converting enzyme inhibitor, 261, 321, 398 Angiotensinogen, 398, 473 Animal model, 22, 26, 28, 68, 73, 281, 321, 398 Anions, 396, 398, 444, 477, 481 Anomalies, 398, 482 Anorexia, 276, 398, 399, 487 Anorexia Nervosa, 276, 399 Anovulation, 25, 40, 71, 399, 465 Antagonism, 73, 399, 407, 413 Antecedent, 47, 399 Anthropometric measurements, 13, 399 Anthropometry, 46, 304, 399 Antibacterial, 399, 479 Antibiotic, 399, 461, 479 Antibodies, Anticardiolipin, 399, 400 Antibodies, Antiphospholipid, 399, 400 Anticoagulant, 255, 283, 399, 400, 469 Antidiabetic, 17, 135, 236, 251, 262, 269, 270, 340, 399, 433 Antidiabetic Agent, 17, 236, 262, 269, 270, 340, 399 Antiemetic, 399, 400, 411 Antigen, 95, 99, 155, 236, 244, 245, 266, 286, 395, 397, 399, 415, 437, 439, 440, 441, 450, 471, 476 Antihypertensive, 261, 321, 400

Anti-inflammatory, 400, 402, 417, 420, 432, 475 Anti-Inflammatory Agents, 400, 402, 417 Antimetabolite, 400, 420 Antineoplastic, 400, 408, 417, 431, 442, 489 Antineoplastic Agents, 400, 442, 489 Antioxidant, 32, 133, 172, 400, 402, 459 Antiphospholipid Syndrome, 135, 399, 400 Antipsychotic, 400, 411, 413, 455 Antipyretic, 400 Antiviral, 393, 400, 420, 443, 461 Antrectomy, 400, 404 Anuria, 400, 445 Aorta, 400, 489 Apnea, 190, 400 Apnoea, 137, 139, 401 Apolipoproteins, 401, 447 Apoptosis, 20, 27, 46, 70, 79, 97, 106, 140, 147, 181, 182, 261, 401 Applicability, 220, 401 Approximate, 18, 139, 401 Aqueous, 96, 242, 243, 253, 267, 401, 403, 409, 419, 424, 438, 446 Arachidonic Acid, 76, 283, 401, 424, 446, 468 Arcuate Nucleus, 35, 401 Arginine, 30, 49, 68, 122, 172, 185, 191, 206, 255, 288, 401, 456, 486 Aromatase, 155, 401 Aromatic, 58, 275, 401, 412, 451, 462, 480 Arterial, 37, 133, 143, 148, 234, 400, 401, 408, 412, 416, 439, 469, 482 Arteries, 228, 239, 240, 365, 398, 400, 401, 402, 405, 406, 417, 448, 451, 453, 470, 483 Arteriography, 222, 401 Arteriolar, 401, 406, 473 Arterioles, 401, 402, 405, 408, 451, 453 Arteriolosclerosis, 401, 402 Arteriosclerosis, 162, 166, 183, 269, 401, 439 Articular, 151, 402, 458 Artificial Pancreas, 274, 402 Ascorbic Acid, 83, 258, 259, 402, 438 Aspartate, 92, 402 Aspartic, 252, 402, 425 Aspartic Acid, 252, 402 Aspirin, 48, 247, 360, 402 Assay, 110, 136, 402, 440, 471 Asymptomatic, 10, 402, 460 Ataxia, 351, 354, 402, 483 Atherogenic, 29, 150, 402

Index 493

ATP, 25, 76, 95, 100, 113, 121, 278, 292, 394, 402, 422, 431, 432, 434, 448, 463, 469, 471, 485 Atrial, 402, 417, 486 Atrioventricular, 402, 417 Atrium, 402, 417, 486, 489 Atrophy, 59, 293, 354, 402, 447 Atropine, 30, 402, 404 Attenuated, 4, 402, 421 Atypical, 102, 402, 413 Autoantibodies, 37, 83, 373, 399, 403 Autoantigens, 244, 403 Autodigestion, 403, 460 Autoimmune disease, 218, 373, 399, 403 Autoimmunity, 37, 237, 373, 403 Autologous, 258, 403 Autonomic, 184, 238, 393, 400, 403, 404, 456, 461, 481 Autosuggestion, 403, 440 Avidin, 266, 403 Axillary, 403, 406, 452 Axillary Artery, 403, 406 B Bacterial Physiology, 394, 403 Bacterial toxin, 266, 403 Bactericidal, 403, 427 Bacteriophage, 403, 464, 485 Bacterium, 403, 414, 436 Basal Ganglia, 400, 402, 403, 439 Basal Ganglia Diseases, 402, 403, 439 Base, 5, 64, 102, 143, 313, 394, 403, 408, 420, 431, 444, 445, 462, 465, 482, 487 Basophils, 403, 434, 446, 465 Belladonna, 402, 404 Benign, 391, 401, 404, 435, 455 Benzene, 404, 444 Beta-pleated, 397, 404 Bilateral, 114, 404, 465 Bile, 264, 404, 411, 430, 431, 433, 447, 467, 480, 482, 487 Bile Acids, 264, 404, 480, 482 Bile Acids and Salts, 404 Bile Ducts, 404, 431, 467 Biliary, 404, 411, 460 Biliary Tract, 404, 460 Biliopancreatic Diversion, 145, 404 Bilirubin, 396, 404, 430, 433 Binding Sites, 33, 99, 272, 404 Bioavailability, 28, 243, 267, 290, 404 Bioengineering, 316, 346, 404 Biogenesis, 63, 97, 404 Biological response modifier, 404, 405, 443

Biological therapy, 405, 435 Biological Transport, 405, 421 Biomarkers, 28, 186, 405 Biomass, 285, 405 Biophysics, 49, 54, 66, 405 Biopsy, 30, 219, 405, 461 Biosynthesis, 41, 47, 63, 78, 87, 92, 93, 95, 205, 210, 271, 401, 405, 469, 477 Biotechnology, 80, 108, 160, 164, 265, 266, 304, 311, 334, 347, 350, 354, 355, 405 Biotin, 74, 168, 169, 258, 403, 405 Biphasic, 13, 16, 405 Bivalent, 405, 451 Bladder, 405, 441, 469, 487 Blastocyst, 89, 159, 163, 405, 415, 464, 486 Bloating, 405, 431, 444 Blood Coagulation, 405, 407, 483 Blood Glucose, 3, 4, 5, 8, 9, 10, 11, 12, 14, 15, 17, 20, 23, 34, 35, 40, 58, 63, 88, 100, 120, 130, 161, 165, 176, 178, 187, 211, 218, 225, 227, 238, 240, 246, 256, 260, 262, 263, 271, 280, 289, 290, 293, 294, 301, 302, 303, 305, 313, 314, 315, 316, 317, 318, 319, 320, 322, 324, 325, 327, 335, 336, 337, 368, 371, 372, 374, 376, 377, 405, 433, 436, 439, 442 Blood-Retinal Barrier, 81, 406 Blot, 209, 285, 406 Body Composition, 15, 52, 64, 121, 203, 223, 406 Body Fluids, 248, 289, 405, 406, 407, 478, 486 Body Mass Index, 8, 17, 27, 28, 46, 277, 406, 459 Bolus, 7, 11, 242, 246, 294, 302, 313, 314, 336, 372, 406 Bolus infusion, 406 Bolus injection, 242, 406 Bone Marrow, 258, 404, 406, 440, 448, 453, 478, 480 Bone scan, 406, 475 Bowel, 397, 406, 421, 443, 457, 458, 462 Bowel Movement, 406, 421 Brachial, 47, 218, 406 Brachial Artery, 47, 218, 406 Bradykinin, 30, 406, 444, 456, 464 Brain Stem, 406, 410, 455 Branch, 387, 406, 418, 424, 460, 470, 479, 483 Breakdown, 81, 406, 420, 421, 431, 458 Breeding, 37, 266, 406 Bronchi, 406, 427, 444, 449, 485

494 Insulin

Bronchiseptica, 406, 462 Bronchoconstriction, 407, 465 Bronchodilator, 407, 444 Buccal, 180, 407, 448 Buformin, 280, 407 Bulimia, 276, 407 Bullous, 181, 407 Burns, 60, 407 Burns, Electric, 407 Bypass, 38, 216, 239, 407, 444, 454 C Cachexia, 276, 277, 407 Caffeine, 172, 200, 205, 407, 471 Calcification, 401, 407 Calcium, 23, 98, 107, 133, 148, 160, 164, 168, 172, 179, 213, 321, 407, 408, 412, 414, 442, 454, 460, 470, 478, 482 Calmodulin, 281, 407, 442 Caloric intake, 45, 407 Calpain, 86, 408 Canonical, 39, 408 Capillary, 26, 75, 406, 408, 432, 447, 489 Capillary Permeability, 406, 408 Capsid, 266, 286, 408 Capsules, 227, 408, 423, 431, 432 Captopril, 376, 408 Carbon Dioxide, 408, 429, 464, 473 Carboplatin, 172, 408 Carboxy, 242, 408 Carcinogen, 408, 427 Carcinogenesis, 28, 203, 408, 411, 463 Carcinogenic, 404, 408, 442, 457, 468, 480 Carcinoma, 124, 408, 418 Cardiac, 56, 93, 159, 163, 178, 179, 181, 208, 243, 274, 279, 295, 407, 408, 417, 419, 427, 453, 454, 459, 480 Cardiac Output, 56, 408, 480 Cardiomyopathy, 245, 291, 292, 295, 408 Cardiorespiratory, 395, 408 Cardiotoxicity, 17, 408 Cardiovascular System, 239, 409 Carnitine, 168, 278, 409 Carotene, 409, 473 Carrier Proteins, 409, 464, 471 Case report, 14, 315, 409, 428 Catabolism, 32, 60, 409 Catalytic Domain, 288, 409 Cataract, 263, 409, 427 Cathepsins, 247, 248, 409 Catheterization, 398, 409, 454 Catheters, 218, 303, 409 Cations, 409, 444

Caudal, 409, 421, 439, 466 Causal, 4, 50, 57, 409 Cause of Death, 25, 237, 249, 265, 409 Caveolae, 23, 409 Caveolins, 409, 413 Cecum, 46, 410, 445 Cell Adhesion, 65, 410 Cell Cycle, 49, 410, 418, 488 Cell Death, 27, 92, 253, 279, 401, 410, 454 Cell Differentiation, 109, 240, 254, 258, 279, 410, 478 Cell Division, 94, 354, 403, 410, 419, 435, 452, 464, 468, 476, 479 Cell membrane, 41, 103, 275, 405, 409, 410, 420, 428, 442, 444, 463, 466 Cell Membrane Structures, 409, 410 Cell proliferation, 66, 112, 186, 279, 323, 402, 410, 478 Cell Respiration, 395, 410, 452, 459, 473 Cell Survival, 181, 205, 259, 410, 435 Cell Transplantation, 34, 268, 318, 410 Cellulose, 410, 430, 464 Central Nervous System, 27, 42, 393, 404, 407, 410, 411, 413, 431, 433, 435, 446, 458, 477 Central Nervous System Infections, 410, 435 Ceramide, 78, 102, 410 Cerebellar, 27, 402, 410, 472, 486 Cerebellum, 28, 410, 472 Cerebral, 68, 142, 402, 403, 406, 411, 416, 427, 428, 449, 454, 481, 483 Cerebral Aqueduct, 411, 481, 483 Cerebrovascular, 29, 280, 297, 403, 409, 411, 483 Cerebrum, 411, 464, 486 Character, 300, 301, 411, 419 Chemoprevention, 28, 411 Chemopreventive, 28, 411 Chemotherapy, 172, 411 Chenodeoxycholic Acid, 411, 487 Chimera, 43, 411 Chimeric Proteins, 286, 411 Chlorophyll, 411, 430 Chloroplasts, 285, 411 Chlorpromazine, 411 Cholecystokinin, 76, 159, 162, 411 Cholera, 80, 118, 266, 285, 411, 489 Cholera Toxin, 118, 266, 285, 411 Choleretic, 264, 411, 487 Cholestasis, 264, 411 Cholesterol Esters, 412, 447

Index 495

Cholinergic, 269, 400, 412, 456 Choriocarcinoma, 155, 412, 437 Choroid, 412, 473 Chromatin, 401, 412, 456 Chromium, 115, 168, 179, 203, 412 Chromosomal, 397, 412, 474, 475 Chromosome, 155, 201, 237, 412, 435, 447, 475, 476 Chronic Disease, 158, 162, 248, 277, 320, 364, 366, 407, 412, 414 Chronic renal, 249, 412, 465, 487 Chylomicrons, 412, 447 Chymotrypsin, 267, 412 Circulatory system, 241, 412, 425 CIS, 35, 49, 66, 175, 261, 412, 473 Citric Acid, 172, 412 Citrus, 402, 412 Clamp, 24, 25, 26, 27, 30, 38, 47, 48, 51, 54, 64, 110, 125, 138, 217, 224, 225, 412 Clathrin, 91, 413, 425 Claudication, 37, 413 Claviceps, 413, 475 Clear cell carcinoma, 413, 420 Clinical Medicine, 300, 308, 328, 413, 467 Clinical Protocols, 67, 413 Clinical trial, 9, 19, 20, 215, 230, 260, 285, 317, 347, 373, 413, 416, 453, 456, 461, 470, 471 Clone, 35, 37, 413 Cloning, 33, 84, 85, 87, 97, 201, 252, 405, 413 Clozapine, 121, 413 Coagulation, 255, 400, 405, 413, 464, 484 Coated Vesicles, 413, 425 Cod Liver Oil, 413, 424 Codon, 285, 413, 431 Coenzyme, 192, 402, 413 Cofactor, 414, 469, 483 Collagen, 182, 414, 416, 429, 431, 438, 465, 468, 479 Collagen disease, 414, 438 Collapse, 398, 406, 414, 478 Colloidal, 253, 395, 414, 424, 462, 477, 481 Colonoscopy, 46, 414 Colorectal, 45, 141, 148, 188, 203, 414 Colorectal Cancer, 45, 141, 148, 188, 414 Colostrum, 121, 192, 414 Combination Therapy, 114, 236, 307, 318, 414, 427 Comorbidity, 131, 414 Competency, 336, 414 Complement, 414, 415, 431, 449, 464, 476

Complementary and alternative medicine, 171, 198, 415 Complementary medicine, 171, 415 Complete remission, 415, 473 Computational Biology, 347, 350, 415 Computed tomography, 222, 415, 475 Computerized axial tomography, 415, 475 Computerized tomography, 415 Conception, 55, 412, 415, 416, 429, 480 Concomitant, 18, 21, 23, 37, 160, 164, 415 Cones, 415, 473 Confusion, 389, 415, 439, 455, 487 Congestive heart failure, 117, 244, 415 Conjugated, 117, 175, 185, 201, 404, 411, 416, 418, 456, 457 Connective Tissue, 76, 400, 402, 406, 414, 416, 429, 431, 451, 470, 474, 480, 482 Connective Tissue Cells, 416 Connective Tissue Diseases, 400, 416 Consciousness, 390, 397, 416, 419, 422 Consolidation, 294, 416 Constipation, 400, 416, 444, 477 Constriction, 416, 444, 475, 488 Consultation, 224, 416 Consumption, 4, 6, 41, 256, 303, 321, 332, 416, 423, 457, 473 Contamination, 259, 416 Continuum, 75, 416 Contraception, 125, 416 Contraceptive, 416, 420 Contraceptive Agents, 416, 420 Contraindications, ii, 416 Control group, 11, 45, 220, 229, 416 Conventional therapy, 416 Conventional treatment, 300, 416 Convulsions, 390, 416, 423, 439 Coordination, 410, 416 Cor, 120, 416, 417, 468 Coronary, 29, 46, 55, 132, 207, 208, 216, 235, 265, 277, 296, 297, 300, 303, 322, 323, 409, 417, 451, 453 Coronary Arteriosclerosis, 417, 453 Coronary heart disease, 132, 235, 297, 300, 303, 323, 409, 417 Coronary Thrombosis, 417, 451, 453 Corpus, 417, 448, 467, 483 Corpus Luteum, 417, 448, 467 Cortex, 402, 417, 428, 437, 454, 472 Cortical, 172, 417, 428, 476, 483 Corticosteroid, 417, 467 Corticotropin-Releasing Hormone, 120, 417

496 Insulin

Cortisol, 120, 138, 396, 417 Cortisone, 417, 420 Coumarin, 417 Coumestrol, 186, 417 Cranial, 410, 418, 435, 458, 461 Craniocerebral Trauma, 403, 418, 435, 483 Crossing-over, 418, 472 Croton Oil, 418, 463 Cues, 142, 418 Culture Media, 259, 395, 418 Cultured cells, 60, 74, 290, 418 Curative, 418, 456, 483 Cyclic, 42, 94, 119, 262, 394, 407, 408, 418, 435, 456, 463, 469 Cyclin, 110, 418 Cyproterone, 127, 418, 430 Cyproterone Acetate, 127, 418 Cysteine, 56, 288, 393, 408, 418, 422, 425 Cystine, 418, 422 Cytochrome, 401, 418 Cytogenetics, 418, 475 Cytokine, 38, 73, 98, 140, 213, 279, 419 Cytoplasm, 401, 404, 410, 411, 419, 434, 442, 451, 453, 454, 455, 456, 474, 488 Cytoskeletal Proteins, 408, 413, 419 Cytoskeleton, 419, 452 Cytotoxic, 419, 478 Cytotoxins, 285, 419 D Dairy Products, 419, 475 Databases, Bibliographic, 347, 419 Deamination, 419, 487 Decidua, 419, 452, 464 Decision Making, 11, 419 Decompensation, 96, 303, 419 Degenerative, 43, 419, 436, 458, 474 Dehydration, 411, 419 Deletion, 30, 35, 48, 72, 73, 78, 401, 419, 431 Delivery of Health Care, 419, 435 Dementia, 261, 269, 400, 419, 455 Dendrites, 419, 455 Density, 27, 44, 84, 87, 113, 183, 234, 296, 321, 406, 420, 423, 447, 457, 465, 479 Dental Caries, 420 Deoxyglucose, 60, 420 Deoxyribonucleic, 420, 474 Deoxyribonucleic acid, 420, 474 Depolarization, 420, 478 Dermatitis, 245, 420 DES, 102, 420 Desensitization, 31, 92, 329, 420

Desogestrel, 127, 420 Deuterium, 420, 438 Dexamethasone, 202, 258, 420 DHEA, 29, 193, 333, 420 Diabetes Insipidus, 243, 287, 420, 438 Diabetic Ketoacidosis, 302, 348, 420, 445 Diabetic Retinopathy, 250, 254, 263, 291, 292, 295, 373, 420, 463 Diagnostic procedure, 233, 334, 421, 462 Diarrhea, 238, 404, 421, 444 Diastolic, 421, 439 Diencephalon, 421, 439, 455, 483 Dietary Fats, 370, 421, 447 Dietary Fiber, 187, 374, 421 Dietitian, 301, 335, 370, 371, 421 Diffusion, 95, 240, 405, 408, 421 Digestion, 4, 54, 290, 396, 404, 406, 421, 431, 443, 447, 480 Digestive system, 231, 239, 303, 421 Digestive tract, 239, 421, 478 Digitalis, 421, 459 Dihydrotestosterone, 418, 421, 472, 477 Dihydroxy, 396, 421, 490 Dilatation, 398, 421, 467, 488 Dilatation, Pathologic, 421, 488 Dilated cardiomyopathy, 178, 421 Dilation, 406, 421, 488 Dilution, 273, 421 Dimerization, 286, 421 Diploid, 421, 464 Discrimination, 363, 421 Disease Progression, 235, 323, 422 Disease Vectors, 422, 442 Disinfectant, 422, 427 Dispenser, 238, 239, 274, 422 Dissociation, 87, 395, 422 Distal, 270, 391, 422, 444, 445, 470 Disulphide, 275, 422 Diuresis, 407, 422 Diuretic, 290, 422, 438, 479 Diurnal, 9, 422 Dizziness, 379, 390, 422 DNA Topoisomerase, 422, 431 Dominance, 199, 422, 427 Dopamine, 400, 411, 413, 422, 462 Dosage Forms, 283, 284, 422 Dose-dependent, 23, 423 Doxazosin, 122, 423 Drug Interactions, 341, 423 Drug Resistance, 286, 423 Drug Tolerance, 423, 484 Drug Utilization, 315, 423

Index 497

Duodenum, 404, 412, 423, 431, 444, 460, 480 Dyes, 397, 404, 423, 456 Dynein, 91, 423 Dyslipidemia, 14, 38, 48, 52, 90, 216, 234, 247, 265, 298, 303, 321, 323, 423 Dyspareunia, 423, 427 Dysplasia, 354, 423 Dyspnea, 419, 423 Dystrophy, 248, 354, 423 E Eating Disorders, 188, 303, 423 Echocardiography, 119, 423 Eclampsia, 56, 423 Edema, 419, 421, 423, 438, 454, 467, 487 Effector, 64, 100, 287, 393, 414, 424, 456, 463 Efficacy, 8, 18, 20, 64, 79, 147, 209, 211, 213, 216, 219, 225, 226, 227, 230, 240, 268, 373, 424 Eicosanoids, 283, 424 Elasticity, 401, 417, 424 Elastin, 414, 416, 424 Elective, 54, 102, 148, 216, 424 Electrocoagulation, 413, 424 Electrolyte, 159, 163, 396, 417, 424, 445, 466, 478, 487 Electrons, 400, 403, 424, 444, 449, 459, 471 Electrophoresis, 26, 424 Electrophysiological, 424, 489 Elementary Particles, 424, 449, 470 Embolus, 424, 441 Embryo, 50, 86, 405, 410, 424, 441, 453 Emulsion, 67, 424, 430 Enamel, 420, 424 Encephalopathy, 259, 425 Endarterectomy, 398, 425 Endemic, 411, 425, 449, 479 Endocrine System, 425, 455 Endocytosis, 44, 74, 91, 409, 425 Endometrial, 28, 75, 425 Endometrium, 28, 419, 425, 450, 452, 486 Endopeptidases, 409, 425, 469 Endorphins, 425, 468 Endoscope, 425, 445 Endosomes, 43, 425 Endothelial cell, 55, 96, 134, 406, 425, 483 Endothelium, 29, 38, 47, 138, 154, 183, 228, 229, 425, 456, 464 Endothelium, Lymphatic, 425 Endothelium, Vascular, 425 Endothelium-derived, 229, 425, 456

Endotoxic, 425, 447 Endotoxin, 104, 425, 486 End-stage renal, 412, 426, 465 Energy balance, 426, 446 Energy Intake, 45, 426 Enhancer, 24, 97, 256, 284, 286, 293, 426 Enkephalin, 426, 468 Enteral Nutrition, 182, 426 Enteropeptidase, 426, 486 Environmental Exposure, 426, 457 Environmental Health, 346, 348, 426 Enzymatic, 266, 288, 407, 409, 415, 420, 426, 427, 429, 473 Enzyme Inhibitors, 269, 426, 464 Ependyma, 401, 426, 483 Ependymal, 426, 481 Epidemic, 57, 72, 323, 426, 479 Epidemiological, 6, 41, 46, 208, 234, 426, 428 Epidermal, 65, 124, 159, 163, 174, 200, 210, 286, 426, 450 Epidermal Growth Factor, 65, 159, 163, 174, 200, 210, 286, 426 Epidermis, 426 Epigastric, 426, 459 Epinephrine, 42, 110, 205, 210, 394, 422, 426, 444, 456, 487 Epistasis, 39, 427 Epithelial, 42, 88, 97, 203, 240, 394, 405, 411, 419, 426, 427 Epithelial Cells, 42, 88, 97, 240, 411, 426, 427 Epithelium, 240, 268, 412, 425, 427, 474 Epitope, 86, 90, 427 Ergot, 427, 475 Erythema, 427, 487 Erythrocytes, 86, 398, 406, 408, 427, 472, 476 Esophagus, 421, 427, 449, 480 Essential Tremor, 354, 427 Esterification, 62, 427 Estradiol, 29, 30, 427, 477 Estrogen, 28, 30, 75, 124, 178, 334, 401, 418, 427, 428, 450, 468, 471, 476, 482, 490 Estrogen receptor, 30, 124, 427 Estrogen Replacement Therapy, 30, 427 Estrone, 28, 427 Ethanol, 27, 41, 427, 429 Ethanolamine, 259, 427 Ethnic Groups, 19, 428 Eukaryotic Cells, 419, 428, 458, 487 Evacuation, 416, 428, 431

498 Insulin

Evoke, 26, 428, 480 Excitatory, 428, 433 Excrete, 400, 428, 445 Exemestane, 114, 428 Exhaustion, 63, 399, 428, 449 Exocrine, 411, 428, 459 Exocytosis, 50, 91, 92, 94, 106, 146, 281, 428 Exon, 49, 281, 396, 428 Expiration, 375, 428, 473 Extensor, 428, 470 Extracellular, 51, 56, 83, 88, 261, 268, 279, 397, 416, 425, 428, 429, 451, 458, 478, 482 Extracellular Matrix, 416, 428, 429, 458 Extracellular Space, 261, 428, 451 Extraction, 19, 266, 428 Extremity, 38, 210, 428 Eye Infections, 394, 428 F Family Planning, 347, 428 Fat, 5, 12, 15, 19, 24, 27, 30, 35, 38, 40, 43, 44, 45, 46, 48, 49, 52, 55, 57, 59, 60, 63, 70, 71, 72, 73, 78, 109, 110, 123, 124, 125, 130, 135, 139, 150, 151, 158, 170, 172, 173, 176, 177, 186, 187, 202, 204, 205, 207, 212, 213, 223, 224, 229, 230, 234, 245, 247, 248, 251, 265, 270, 272, 276, 277, 281, 282, 288, 303, 311, 316, 318, 322, 323, 336, 375, 393, 394, 398, 401, 404, 406, 409, 410, 414, 416, 417, 424, 428, 429, 444, 446, 447, 453, 457, 458, 459, 466, 474, 475, 478, 481, 486 Fatal Outcome, 428, 471 Fatigue, 429, 436 Fatty Liver, 175, 183, 429 Fermentation, 171, 176, 286, 429 Ferrets, 182, 429 Fetal Blood, 429, 464 Fetus, 32, 429, 440, 464, 467, 488 Fibrillation, 140, 429 Fibrin, 405, 429, 464, 483 Fibrinogen, 429, 464, 483 Fibrinolysis, 234, 429 Fibroblasts, 43, 50, 59, 80, 416, 429, 443, 479 Fibrosis, 138, 277, 354, 429, 476 Filtration, 260, 429, 445 Fistula, 429, 457 Fixation, 429, 476 Flatus, 430, 431 Fluorescence, 43, 100, 430 Flutamide, 125, 135, 430 Folate, 160, 163, 430

Fold, 75, 254, 255, 267, 279, 285, 286, 323, 430 Folic Acid, 430 Food Habits, 313, 430 Food Preferences, 335, 337, 430 Food Technology, 430 Foot Care, 327, 375, 430 Foot Ulcer, 295, 430 Foramen, 430, 462 Forearm, 29, 118, 218, 405, 430 Fossa, 410, 430 Fructose, 21, 31, 173, 430, 434, 443 Fungus, 427, 430, 475, 490 G Gallbladder, 222, 393, 404, 411, 421, 430, 431 Gallstones, 277, 404, 411, 430, 487 Ganglia, 393, 403, 431, 455, 461, 481 Ganglioside, 285, 431 Gangrene, 249, 431 Gas, 218, 222, 397, 408, 421, 428, 430, 431, 438, 444, 456, 481, 488 Gastric, 36, 58, 159, 162, 186, 248, 270, 403, 409, 422, 426, 431 Gastric Acid, 271, 431 Gastric Emptying, 159, 162, 186, 270, 431 Gastrin, 58, 431, 437 Gastrointestinal tract, 23, 283, 427, 431, 446, 477, 479, 486 Gastroparesis, 15, 361, 431 Gastrostomy, 426, 431 Gelatin, 418, 431, 433, 483 Gene Deletion, 78, 100, 431 Genetic Code, 431, 457 Genetic Engineering, 405, 413, 431 Genetic testing, 219, 431 Genetics, 38, 39, 78, 126, 158, 161, 164, 237, 238, 313, 314, 373, 418, 422, 431 Genistein, 186, 431 Genotype, 109, 205, 277, 432, 462 Geriatric, 315, 432 Germ Cells, 432, 457, 459, 482 Gestation, 54, 432, 464, 467 Gestational, 27, 54, 113, 114, 131, 132, 147, 162, 166, 188, 225, 236, 305, 319, 370, 374, 432 Gestational Age, 113, 114, 147, 432 Ginseng, 191, 192, 193, 194, 196, 432 Gland, 208, 248, 394, 417, 432, 438, 459, 460, 464, 469, 471, 476, 480, 481, 484 Gliclazide, 280, 432 Glipizide, 18, 194, 280, 432

Index 499

Glomerular, 260, 432, 443, 445 Glomerular Filtration Rate, 260, 432, 445 Glomeruli, 432 Glomerulosclerosis, 290, 432 Glomerulus, 432, 445 Glottis, 432, 437, 462 Glucocorticoid, 120, 152, 420, 432, 438, 452, 467 Glucokinase, 67, 97, 99, 102, 103, 261, 281, 432 Gluconeogenesis, 20, 70, 128, 139, 211, 407, 432 Glucose Clamp Technique, 30, 433 Glucose Intolerance, 26, 40, 41, 64, 90, 149, 320, 420, 433 Glucose Tolerance Test, 6, 13, 19, 26, 27, 29, 42, 46, 47, 48, 55, 77, 200, 203, 225, 235, 359, 433 Glucose-6-Phosphatase, 66, 90, 239, 433 Glucuronic Acid, 255, 433, 436 Glucuronides, 433 Glutamate, 433 Glutamic Acid, 252, 430, 433, 468 Glutamine, 31, 182, 433 Glutathione Peroxidase, 184, 433, 476 Glyburide, 194, 269, 280, 340, 433 Glycerol, 94, 433, 463 Glycerophospholipids, 433, 463 Glycine, 404, 411, 433, 477 Glycogen Synthase, 40, 70, 89, 99, 113, 208, 251, 269, 434 Glycolysis, 407, 434 Glycoprotein, 74, 153, 266, 429, 434, 453, 477, 483, 486 Glycosaminoglycans, 255, 434, 470 Glycoside, 434, 459, 475 Glycosidic, 434, 457, 463 Glycosuria, 265, 312, 434 Glycosylation, 31, 87, 434 Gonad, 434 Gonadal, 51, 227, 240, 351, 434, 480 Gonadotropin, 51, 127, 412, 434 Governing Board, 434, 467 Gp120, 434, 461 Grade, 300, 374, 434 Graft, 38, 434, 437, 441, 454 Graft Rejection, 434, 441 Grafting, 114, 434, 441 Granule, 28, 434, 474 Granulocytes, 434, 478, 490 Granulosa Cells, 153, 435, 448 Grasses, 413, 430, 435, 436

Growth factors, 45, 79, 123, 142, 149, 243, 252, 253, 259, 279, 285, 435, 442 Guanylate Cyclase, 435, 456 H Habitual, 411, 435 Half-Life, 111, 278, 279, 435 Haploid, 435, 464 Haptens, 395, 435, 471 Headache, 379, 390, 407, 435, 439, 477 Headache Disorders, 435 Health Care Costs, 237, 435 Health Education, 45, 374, 435 Health Expenditures, 435 Health Promotion, 283, 364, 366, 377, 435 Health Services, 419, 435 Heart attack, 13, 221, 409, 436 Heart failure, 119, 131, 148, 332, 436 Heme, 133, 404, 418, 436, 459, 466 Hemochromatosis, 26, 436 Hemodialysis, 436, 445 Hemodynamics, 57, 260, 436 Hemoglobin, 5, 9, 15, 17, 75, 254, 318, 373, 398, 427, 436, 446 Hemoglobinuria, 354, 436 Hemolytic, 436, 471 Hemorrhage, 418, 424, 435, 436, 454, 480, 489 Heparin, 30, 65, 67, 129, 255, 436 Hepatitis, 266, 286, 436 Hepatocellular, 149, 436 Hepatocellular carcinoma, 149, 436 Hepatocyte, 66, 74, 89, 90, 411, 436 Hepatoma, 48, 86, 144, 436 Herbicides, 253, 436 Hereditary, 296, 416, 436, 474 Heredity, 431, 436 Heritability, 38, 137, 437 Heterodimer, 253, 437 Heterogeneity, 395, 437 Hiccup, 411, 437 Hippocampus, 437, 455 Hirsutism, 418, 437, 438 Histology, 437, 455 Homogeneous, 401, 416, 437, 462 Homologous, 39, 90, 220, 252, 261, 270, 288, 396, 405, 418, 437, 442, 476, 482 Homozygotes, 26, 422, 437 Hormonal, 31, 32, 35, 40, 47, 58, 71, 79, 138, 204, 239, 245, 290, 317, 402, 417, 427, 437 Hormone therapy, 437, 450

500 Insulin

Host, 239, 259, 403, 422, 437, 440, 446, 474, 475, 488, 489 Human growth hormone, 23, 437, 479 Hybrid, 33, 61, 87, 107, 279, 413, 437, 475 Hybridomas, 437, 443 Hydatidiform Mole, 412, 437 Hydrochlorothiazide, 116, 438 Hydrocortisone, 259, 438 Hydrogen, 224, 256, 295, 393, 403, 408, 420, 433, 438, 447, 452, 459, 470, 481 Hydrogen Bonding, 256, 438 Hydrogen Peroxide, 433, 438, 447, 481 Hydrolysis, 76, 240, 402, 438, 447, 463, 466, 470, 486 Hydrophilic, 288, 289, 438 Hydrophobic, 96, 252, 278, 433, 438, 447 Hydroxylysine, 414, 438 Hydroxyproline, 414, 438 Hyperammonemia, 352, 438 Hyperandrogenism, 25, 40, 125, 135, 227, 438 Hypercholesterolemia, 189, 234, 263, 423, 438 Hyperglycaemia, 289, 438 Hyperlipidemia, 227, 234, 241, 263, 277, 296, 297, 423, 438 Hyperlipoproteinemia, 438, 439, 447 Hyperphagia, 35, 438 Hyperplasia, 28, 353, 438 Hypersensitivity, 87, 396, 397, 420, 439, 446, 474, 476 Hypertriglyceridemia, 129, 229, 234, 296, 423, 439 Hypertrophy, 179, 417, 439, 486 Hyperuricemia, 296, 297, 439 Hypodermic, 312, 439 Hypoglycaemia, 112, 148, 161, 165, 439 Hypoglycemic Agents, 13, 114, 131, 162, 166, 249, 263, 280, 292, 329, 439 Hypogonadism, 51, 439 Hypokinesia, 439, 460 Hypophyseal, 439 Hypoplasia, 27, 439 Hypotension, 400, 416, 439, 465 Hypothalamic, 21, 24, 36, 51, 120, 127, 227, 439, 479 Hypothalamus, 24, 35, 401, 417, 421, 426, 439, 464, 468, 479, 483 Hypothermia, 439 Hypoxanthine, 439, 490 Hypoxia, 81, 145, 204, 439, 483 Hysteria, 179, 439

I Iatrogenic, 264, 439 Ice Cream, 303, 440 Id, 167, 187, 359, 360, 361, 363, 364, 367, 379, 386, 388, 440 Ileum, 270, 410, 440, 444, 490 Imidazole, 277, 405, 440 Immaturity, 301, 440 Immune response, 272, 394, 399, 403, 417, 434, 435, 440, 449, 476, 481, 488, 489 Immune Sera, 440 Immune system, 218, 221, 266, 373, 403, 405, 440, 446, 448, 449, 488, 490 Immune Tolerance, 218, 244, 440 Immunity, 152, 419, 440, 457, 485 Immunization, 266, 286, 440, 467, 476 Immunoassay, 126, 399, 440 Immunodeficiency, 134, 137, 259, 354, 440 Immunogenic, 16, 266, 440, 447, 471 Immunoglobulin, 399, 440, 453 Immunologic, 16, 243, 267, 279, 432, 440 Immunology, 118, 394, 395, 440 Immunosuppressive, 229, 432, 440 Immunosuppressive therapy, 440 Immunotherapy, 220, 405, 420, 440 Impairment, 21, 29, 41, 62, 75, 90, 221, 251, 265, 315, 320, 402, 411, 428, 441, 450 Implantation, 34, 415, 441, 486 Incision, 441, 443 Incontinence, 441, 458 Incubated, 54, 441 Incubation, 441, 462 Incubation period, 441, 462 Indicative, 235, 274, 304, 441, 460, 488 Induction, 16, 21, 35, 51, 73, 91, 180, 205, 244, 267, 271, 398, 400, 441, 468 Infancy, 129, 353, 441 Infant Mortality, 320, 441 Infantile, 441, 447 Infarction, 216, 441, 473 Infection, 33, 52, 257, 325, 326, 369, 404, 405, 428, 440, 441, 446, 448, 455, 461, 462, 471, 474, 480, 488, 490 Infertility, 25, 40, 59, 71, 248, 441 Infuse, 441, 442 Infusion Pumps, 34, 348, 442 Ingestion, 4, 161, 165, 200, 219, 433, 438, 442, 460, 465, 482 Inhalation, 226, 289, 395, 437, 442, 465 Initiation, 52, 103, 106, 286, 373, 442, 485 Inlay, 442, 473 Inorganic, 136, 394, 442

Index 501

Inositol, 25, 40, 86, 91, 93, 94, 96, 99, 133, 253, 442 Inositol 1,4,5-Trisphosphate, 86, 442 Inotropic, 160, 164, 422, 442 Inpatients, 127, 442 Insecticides, 253, 442, 462 Insight, 6, 30, 36, 48, 70, 79, 81, 117, 134, 442 Insomnia, 442, 477 Insulin Infusion Systems, 305, 442 Insulin-Like Growth Factor-Binding Protein 2, 115, 442 Interferon, 213, 221, 443 Interferon-alpha, 443 Interleukin-1, 72, 443 Interleukin-2, 443 Interleukin-4, 83, 213, 443 Interleukin-6, 72, 205, 213, 443 Intermediate Filaments, 443, 455 Intermittent, 12, 38, 260, 277, 443 Interstitial, 12, 428, 443 Intestinal, 42, 88, 261, 280, 285, 409, 411, 426, 433, 443, 449 Intestine, 262, 404, 406, 414, 443, 445 Intoxication, 443, 488 Intramuscular, 133, 153, 253, 443, 460 Intraperitoneal, 253, 443 Intravenous, 6, 9, 19, 26, 46, 47, 55, 77, 130, 225, 226, 253, 256, 260, 406, 441, 442, 443, 460 Intrinsic, 65, 104, 395, 443 Inulin, 432, 443 Invasive, 34, 222, 268, 437, 440, 443, 449 Invertebrates, 422, 432, 444 Involuntary, 403, 427, 429, 444, 454, 464, 477, 478 Ion Exchange, 410, 444 Ions, 256, 403, 407, 422, 424, 438, 442, 444, 452, 466, 470 Irritable Bowel Syndrome, 444, 458 Ischemia, 37, 211, 263, 295, 402, 431, 444, 454, 473 Isoflavones, 178, 185, 444 Isoproterenol, 30, 99, 444 Isotonic, 18, 444, 452 Isozymes, 49, 444, 471 J Jejunoileal Bypass, 404, 444 Jejunostomy, 426, 444 Jejunum, 404, 444 Joint, 402, 444, 458, 481, 482

K Kallidin, 406, 444 Kb, 35, 346, 444 Keratolytic, 420, 444 Keto, 32, 444 Ketone Bodies, 420, 444, 445 Ketonuria, 300, 445 Ketosis, 420, 445 Kidney Cortex, 445, 451 Kidney Failure, 221, 426, 432, 445 Kidney Failure, Acute, 445 Kidney Failure, Chronic, 445 Kinetics, 32, 96, 125, 146, 160, 164, 204, 445 L Labile, 267, 353, 414, 445 Lactation, 210, 414, 445, 468 Laparoscopy, 222, 445 Large Intestine, 410, 414, 421, 443, 445, 472, 478 Larva, 445, 451 Laryngoscopy, 146, 184, 445 Larynx, 432, 445, 485 Latent, 445, 467 Least-Squares Analysis, 446, 472 Lens, 409, 446, 489 Leprosy, 430, 446 Leptin, 21, 24, 35, 52, 73, 90, 96, 99, 102, 115, 121, 127, 134, 140, 141, 160, 164, 174, 176, 201, 203, 206, 208, 282, 446 Lesion, 72, 430, 446, 448, 477 Lethal, 281, 403, 446 Leucine, 160, 164, 446 Leukemia, 354, 446 Leukocytes, 403, 406, 434, 443, 446, 453, 456, 486 Leukotrienes, 283, 401, 424, 446 Levo, 446, 490 Libido, 398, 446 Library Services, 386, 446 Life cycle, 405, 445, 446, 457, 470 Ligament, 245, 446, 469 Ligands, 44, 56, 65, 78, 112, 279, 307, 446 Ligation, 35, 446 Likelihood Functions, 446, 472 Linear Models, 446, 472 Linkage, 45, 314, 447 Lipase, 195, 447, 458 Lipid, 21, 30, 38, 45, 46, 52, 53, 56, 62, 65, 72, 79, 84, 99, 121, 122, 125, 134, 139, 141, 153, 162, 166, 175, 180, 185, 201, 203, 204, 234, 235, 238, 240, 272, 280,

502 Insulin

282, 364, 401, 408, 409, 433, 442, 444, 447, 458, 459, 486 Lipid A, 21, 46, 52, 125, 447, 458 Lipid Peroxidation, 447, 459 Lipodystrophy, 52, 134, 180, 223, 447 Lipolysis, 27, 52, 65, 110, 210, 447 Lipophilic, 242, 447 Lipopolysaccharides, 253, 447, 474 Lipoprotein, 84, 87, 107, 113, 177, 183, 234, 235, 240, 321, 423, 447, 448 Lipoprotein Lipase, 107, 447 Lipoprotein(a), 113, 447 Lipoxygenase, 446, 447 Liver Cirrhosis, 112, 148, 189, 447 Liver scan, 447, 475 Liver Transplantation, 112, 448 Lobe, 437, 448, 468 Localization, 96, 148, 448 Localized, 44, 56, 72, 420, 429, 437, 441, 447, 448, 464, 488 Locomotion, 448, 464 Logistic Models, 448, 472 Longitudinal Studies, 47, 448 Loop, 21, 26, 99, 145, 281, 442, 448 Low-density lipoprotein, 96, 423, 447, 448 Luciferase, 35, 448 Lupus, 190, 399, 400, 448, 482 Luteal Phase, 110, 448, 452 Lutein Cells, 448, 468 Lymph, 403, 412, 425, 448, 449, 481 Lymphatic, 425, 441, 448, 451, 478, 484 Lymphocyte, 400, 448, 449, 450 Lymphoid, 399, 448 Lymphoma, 213, 354, 448 Lysine, 255, 316, 438, 448, 486 Lyssavirus, 448, 471 M Macrophage, 38, 90, 93, 443, 449 Magnetic Resonance Imaging, 38, 222, 224, 449, 475 Magnetic Resonance Spectroscopy, 52, 449 Major Histocompatibility Complex, 105, 443, 449 Malabsorption, 354, 449 Malaria, 104, 449 Malaria, Falciparum, 449 Malaria, Vivax, 449 Malignancy, 393, 449 Malignant, 354, 394, 400, 401, 412, 449, 455, 458, 474, 482 Malignant tumor, 412, 449, 458, 474

Malnutrition, 122, 182, 396, 402, 407, 449, 453 Mammary, 208, 248, 312, 414, 447, 449, 471, 482 Mammogram, 45, 407, 449 Meat, 186, 203, 421, 449, 475 Meat Products, 421, 449 Medial, 4, 402, 449, 458 Mediastinum, 412, 449 Mediate, 43, 65, 66, 73, 79, 82, 106, 161, 165, 201, 279, 288, 422, 450 Mediator, 25, 35, 41, 48, 79, 94, 103, 411, 443, 450, 477 Medicament, 257, 450 MEDLINE, 347, 350, 355, 450 Megestrol, 114, 450 Megestrol Acetate, 114, 450 Melanin, 450, 462, 487 Melanocytes, 450 Melanoma, 354, 450 Melanosis, 393, 450 Membrane Glycoproteins, 450 Membrane Proteins, 409, 450 Memory, 18, 221, 239, 246, 398, 419, 450 Meninges, 410, 418, 450 Menopause, 189, 367, 450, 461, 466, 467 Menstrual Cycle, 71, 211, 448, 450, 467 Menstruation, 367, 397, 419, 448, 450, 457 Mental Disorders, 231, 439, 450, 467 Mental Health, iv, 19, 231, 346, 349, 360, 450, 467, 470 Menthol, 243, 451 Mentors, 47, 451 Mesenchymal, 258, 426, 437, 451 Meta-Analysis, 89, 179, 451 Metabolic disorder, 50, 71, 238, 243, 280, 281, 287, 290, 420, 438, 451 Metabolite, 427, 451, 467 Metallothionein, 42, 451 Metamorphosis, 8, 451, 457 Metaplasia, 182, 451 Metastasis, 132, 174, 391, 451 Metastatic, 114, 451, 476 Methionine, 451, 468 MI, 8, 17, 46, 131, 172, 186, 255, 262, 277, 373, 391, 451 Microbe, 451, 484 Microbiology, 394, 402, 451 Microcirculation, 447, 451, 464 Microdialysis, 12, 451 Microorganism, 414, 451, 460, 490 Micro-organism, 420, 451

Index 503

Microscopy, 43, 50, 56, 91, 452 Microtubule-Associated Proteins, 452, 455 Microtubules, 181, 443, 452, 455 Midaxillary line, 452, 490 Mifepristone, 110, 452 Migration, 93, 154, 178, 323, 452 Milliliter, 452, 487 Millimeter, 452, 490 Mitochondria, 278, 316, 452, 454, 458 Mitochondrial Swelling, 452, 454 Mitosis, 401, 452, 479 Mitotic, 28, 452, 453, 489 Modeling, 19, 96, 272, 452 Modification, 23, 69, 244, 252, 278, 285, 294, 431, 452, 471 Modulator, 69, 452 Molecular Structure, 97, 272, 452 Molecule, 54, 60, 82, 104, 108, 239, 256, 278, 285, 289, 400, 403, 404, 408, 413, 415, 418, 422, 424, 425, 427, 434, 438, 452, 459, 463, 465, 470, 472, 478, 485, 488 Monitor, 179, 217, 218, 273, 313, 333, 452, 456 Monoclonal, 81, 126, 285, 437, 453 Monoclonal antibodies, 126, 285, 453 Monocytes, 211, 443, 446, 453, 465 Monogenic, 314, 453 Mononuclear, 86, 453, 486 Monounsaturated fat, 5, 453 Morphological, 209, 395, 424, 430, 450, 453 Morphology, 23, 309, 409, 453 Morula, 405, 453 Mucolytic, 393, 453 Mucosa, 411, 448, 453, 468, 480 Multicenter study, 216, 453 Muscle Fibers, 453, 454 Muscular Atrophy, 354, 453 Muscular Dystrophies, 423, 453 Musculature, 59, 439, 453 Mutagenesis, 35, 49, 70, 76, 453 Mutagens, 453 Myocardial infarction, 127, 141, 146, 148, 150, 159, 163, 216, 234, 249, 296, 417, 451, 453, 454 Myocardial Ischemia, 263, 453 Myocardial Reperfusion, 454, 473 Myocardial Reperfusion Injury, 454, 473 Myocardium, 234, 451, 453, 454 Myofibrils, 408, 454 Myosin, 160, 164, 454 Myotonic Dystrophy, 354, 454

N Nasogastric, 426, 454 Natural selection, 404, 454 Nausea, 399, 400, 422, 431, 445, 454, 487 NCI, 1, 230, 345, 412, 454 Necrosis, 154, 401, 441, 451, 453, 454, 473 Neocortex, 454, 455 Neonatal, 56, 162, 166, 208, 441, 454 Neoplasia, 45, 354, 454, 455 Neoplasm, 455 Neoplastic, 258, 437, 438, 448, 455 Nephropathy, 17, 235, 249, 250, 254, 260, 263, 265, 280, 291, 292, 297, 321, 373, 376, 445, 455 Nervous System, 240, 310, 354, 395, 404, 410, 450, 455, 461, 471, 481, 482, 488 Networks, 65, 455 Neural, 316, 395, 397, 455 Neuroendocrine, 35, 39, 112, 455 Neurofibrillary Tangles, 269, 455 Neurofilaments, 455 Neuroleptic, 400, 413, 455 Neurologic, 69, 295, 455 Neuromuscular, 393, 455, 487 Neuromuscular Junction, 393, 455 Neuronal, 27, 35, 68, 94, 205, 455, 476 Neurons, 28, 35, 127, 261, 420, 428, 431, 454, 455, 456, 471, 481, 482 Neuropathy, 17, 222, 235, 249, 250, 254, 263, 265, 280, 290, 291, 292, 295, 297, 373, 396, 455 Neuropeptide, 417, 455 Neurosis, 455, 463 Neurotoxicity, 28, 455 Neurotransmitters, 455, 456, 477 Neutralization, 255, 456 Neutropenia, 456, 465 Neutrophils, 434, 446, 456, 465 Niacin, 167, 456, 486 Nicotine, 303, 456 Nitric Oxide, 29, 60, 68, 98, 138, 175, 183, 202, 209, 228, 229, 323, 456 Nitrogen, 201, 244, 396, 398, 429, 433, 445, 456, 486 Nonblinded, 9, 456 Norepinephrine, 394, 422, 456, 477 Nuclear, 36, 49, 66, 77, 89, 90, 91, 182, 285, 303, 403, 424, 428, 454, 456 Nuclear Proteins, 36, 456 Nuclei, 24, 424, 431, 449, 452, 456, 458, 470 Nucleic acid, 239, 251, 261, 276, 286, 408, 431, 439, 453, 456, 457, 471, 474

504 Insulin

Nucleoproteins, 456, 457 Nucleus, 401, 403, 412, 418, 419, 420, 424, 428, 443, 453, 456, 457, 468, 470, 480, 483 Nutritional Status, 39, 457 Nutritive Value, 457 Nymph, 451, 457 O Octreotide, 18, 71, 172, 341, 457 Ocular, 253, 263, 457 Odour, 401, 457, 487 Ointments, 423, 457 Oleic Acids, 270, 457 Oligo, 59, 457 Oligomenorrhea, 457, 465 Oligosaccharides, 193, 457 Oliguria, 445, 457 Omega-3 fatty acid, 178, 228, 457 Oncogene, 124, 128, 153, 162, 166, 268, 354, 457 Oncogenic, 253, 457 Oocytes, 92, 96, 159, 163, 457 Opacity, 409, 420, 457 Opsin, 458, 473 Optic Chiasm, 439, 458 Optic Disk, 421, 458 Optic Nerve, 458, 473, 474 Organ Culture, 458, 484 Organelles, 413, 419, 450, 453, 458, 464 Organoleptic, 458 Orlistat, 151, 458 Orthostatic, 400, 457, 458 Osmotic, 98, 395, 452, 458, 477 Osteoarthritis, 84, 189, 245, 458 Osteoblasts, 91, 458 Osteogenic sarcoma, 458 Osteoporosis, 172, 189, 427, 458, 471 Osteosarcoma, 172, 458 Ouabain, 176, 459 Outpatient, 14, 217, 459 Ovarian Follicle, 417, 435, 459 Ovaries, 142, 401, 438, 459, 465, 472, 477, 482 Ovary, 25, 40, 47, 59, 71, 82, 110, 127, 133, 146, 151, 152, 155, 277, 291, 292, 302, 374, 417, 427, 434, 438, 459, 465, 480 Overdose, 257, 459 Overexpress, 33, 459 Overweight, 5, 6, 27, 57, 121, 126, 166, 217, 223, 224, 225, 245, 276, 459 Ovulation, 25, 71, 303, 399, 435, 448, 450, 459

Ovum, 417, 419, 432, 446, 453, 459, 467, 468, 486, 490 Oxidation, 5, 32, 124, 139, 177, 210, 277, 283, 393, 400, 407, 418, 420, 422, 433, 447, 459, 483 Oxidative metabolism, 118, 395, 446, 459 Oxidative Stress, 20, 32, 109, 175, 183, 184, 185, 201, 203, 459 Oxygenase, 133, 459 P Pacemaker, 273, 459 Palliative, 418, 450, 459, 483 Pancreas Transplant, 316, 358, 459 Pancreatic cancer, 145, 354, 460 Pancreatic Hormones, 240, 252, 460 Pancreatic Juice, 412, 460 Pancreatic Polypeptide, 460 Pancreatitis, 129, 190, 460 Paralysis, 276, 460 Parathyroid, 259, 460, 482 Parathyroid Glands, 460 Parathyroid hormone, 259, 460 Parenteral, 23, 239, 253, 267, 270, 426, 460 Parkinsonism, 261, 400, 460 Paroxysmal, 354, 435, 460, 462, 490 Partial remission, 460, 473 Particle, 23, 287, 460, 479, 485 Parturition, 460, 468 Patch, 334, 460 Pathogen, 267, 441, 460 Pathogenesis, 17, 29, 41, 46, 52, 53, 61, 71, 73, 74, 203, 237, 251, 254, 296, 302, 304, 309, 460 Pathologic, 237, 280, 284, 393, 401, 405, 417, 439, 460, 461, 470, 488 Pathologic Processes, 401, 461 Pathologies, 236, 278, 461 Pathophysiology, 56, 63, 67, 77, 129, 152, 153, 247, 300, 323, 461 Patient Compliance, 34, 461 Patient Education, 18, 210, 301, 326, 327, 367, 376, 377, 384, 386, 391, 461 Patient Selection, 9, 14, 301, 461 Pelvic, 461, 469 Penicillin, 399, 461 Peptide T, 37, 103, 461 Percutaneous, 294, 461 Perfusion, 178, 433, 439, 461, 484 Perimenopausal, 113, 131, 461 Perineal, 245, 461 Perineum, 461 Peripheral Nervous System, 461, 479, 481

Index 505

Peripheral Vascular Disease, 235, 280, 461 Peritoneal, 264, 443, 461 Peritoneal Cavity, 264, 443, 461 Peritoneum, 461, 462 Pertussis, 65, 462, 490 Pesticides, 253, 436, 442, 462 Petrolatum, 424, 462 Pharmaceutical Preparations, 234, 410, 427, 431, 462 Pharmaceutical Solutions, 423, 462 Pharmacodynamic, 288, 462 Pharmacokinetic, 20, 328, 462 Pharmacologic, 7, 51, 64, 66, 418, 435, 462, 484, 485 Phenolphthalein, 424, 462 Phenotype, 40, 67, 71, 78, 153, 205, 259, 431, 462 Phenyl, 290, 462 Phenylalanine, 105, 462, 487 Phlebotomy, 26, 462 Phobia, 303, 463 Phobic Disorders, 463 Phorbol, 66, 102, 463 Phorbol Esters, 66, 102, 463 Phosphodiesterase, 83, 94, 291, 292, 463 Phospholipases, 463, 478 Phospholipids, 76, 93, 158, 253, 399, 400, 428, 442, 447, 463 Phosphorus, 196, 407, 460, 463 Phosphorylase, 263, 408, 463 Phosphorylate, 21, 49, 54, 70, 72, 278, 463 Phosphorylated, 24, 40, 49, 50, 73, 74, 253, 413, 463 Phosphotyrosine, 84, 106, 463 Photocoagulation, 413, 463 Physical Examination, 77, 217, 221, 224, 432, 463 Pigment, 404, 411, 450, 464, 474 Piloerection, 439, 464 Pilot study, 220, 464 Pineal gland, 412, 464 Pituitary Gland, 245, 417, 464, 468 Placenta, 205, 252, 401, 427, 429, 464, 467 Placental tissue, 32, 464 Plaque, 29, 240, 398, 402, 464 Plasma cells, 399, 464 Plasma protein, 395, 425, 464, 470, 477 Plasmin, 464 Plasminogen, 83, 110, 141, 154, 207, 303, 310, 464 Plasminogen Activators, 464 Plasticity, 155, 464

Plastids, 285, 458, 464 Platelet Activating Factor, 295, 465 Platelet Activation, 465, 478 Platelet Aggregation, 176, 456, 465, 483 Platelet-Derived Growth Factor, 89, 99, 178, 465 Platelets, 408, 456, 465, 477, 483 Platinum, 448, 465 Plethysmography, 30, 465 Point Mutation, 73, 110, 465 Poisoning, 427, 443, 454, 465 Polyethylene, 23, 465 Polymerase, 81, 286, 465 Polymers, 465, 469, 480 Polymorphic, 142, 244, 465 Polymorphism, 113, 141, 142, 162, 166, 353, 466 Polyposis, 414, 466 Polysaccharide, 400, 410, 466, 470 Polyunsaturated fat, 174, 183, 283, 466, 483 Porphyria, 462, 466 Porphyria Cutanea Tarda, 462, 466 Port, 146, 238, 348, 466 Port-a-cath, 466 Post partum, 55, 466 Posterior, 397, 402, 410, 412, 452, 459, 466 Postmenopausal, 6, 27, 115, 132, 172, 179, 207, 365, 427, 458, 466, 471 Postnatal, 32, 112, 113, 121, 466, 480 Postprandial Blood Glucose, 4, 245, 466 Postsynaptic, 466, 478, 482 Post-translational, 31, 60, 398, 466, 477 Potassium, 113, 123, 127, 150, 159, 163, 169, 176, 179, 218, 236, 396, 438, 466 Potassium Channels, 113, 466 Potentiate, 279, 289, 466 Potentiation, 127, 178, 184, 201, 206, 311, 466, 478 Practice Guidelines, 349, 467 Precancerous, 411, 467 Precipitation, 96, 467 Predisposition, 245, 467 Prednisolone, 264, 467 Pre-Eclampsia, 56, 467 Pre-eclamptic, 423, 467 Pregnancy Tests, 432, 467 Premenopausal, 174, 178, 467 Prenatal, 424, 467 Primary Biliary Cirrhosis, 109, 467 Primary Prevention, 15, 467 Probe, 49, 222, 451, 467

506 Insulin

Prodrug, 210, 467 Progesterone, 72, 153, 450, 452, 467, 468, 480 Proinsulin, 37, 63, 81, 86, 100, 102, 103, 104, 110, 143, 208, 210, 266, 275, 279, 468, 471 Prolactin, 174, 468 Proline, 316, 414, 438, 468 Pro-Opiomelanocortin, 115, 425, 468 Prophase, 405, 457, 468, 482 Prophylaxis, 284, 289, 290, 468, 488 Proportional, 15, 468 Prospective Studies, 45, 64, 468 Prospective study, 141, 149, 468 Prostaglandin, 283, 468, 483 Prostaglandins A, 468, 469 Prostaglandins F, 452, 469 Prostate, 115, 145, 149, 173, 176, 181, 186, 190, 235, 336, 354, 405, 469, 486 Protease, 54, 144, 210, 414, 469 Protease Inhibitors, 144, 210, 469 Protein Binding, 91, 106, 469, 484 Protein C, 35, 85, 106, 107, 266, 275, 286, 396, 397, 401, 403, 413, 447, 469, 487 Protein Conformation, 397, 469 Protein Isoforms, 396, 469 Protein Kinases, 53, 63, 64, 79, 469 Protein-Tyrosine Kinase, 431, 469 Proteinuria, 260, 321, 432, 467, 469 Proteoglycan, 144, 470 Proteolytic, 32, 270, 396, 414, 426, 429, 464, 470 Prothrombin, 470, 483 Protocol, 13, 38, 43, 222, 223, 294, 470 Protons, 438, 449, 470, 471 Proximal, 35, 94, 208, 422, 444, 445, 470 Psoriasis, 134, 269, 470 Psyllium, 197, 470 Puberty, 47, 213, 295, 470 Public Health, 50, 160, 164, 323, 349, 358, 364, 366, 470 Public Policy, 45, 347, 470 Publishing, 3, 7, 11, 80, 296, 299, 301, 303, 470 Pulmonary, 243, 256, 288, 405, 416, 417, 445, 446, 470, 481, 489 Pulmonary Artery, 405, 470, 489 Pulmonary Edema, 445, 470 Pulmonary hypertension, 417, 470 Pulse, 142, 452, 470 Pupa, 451, 470 Purified Insulins, 468, 471

Purifying, 40, 256, 273, 471 Purines, 471, 477, 490 Putrefaction, 431, 471 Pyruvate Kinase, 42, 471 Q Quality of Life, 37, 111, 118, 122, 139, 200, 216, 336, 471 R Rabies, 266, 448, 471 Rabies Virus, 266, 448, 471 Race, 27, 59, 223, 452, 471 Radiation, 424, 426, 430, 440, 471, 475, 490 Radioactive, 406, 435, 438, 441, 447, 453, 456, 457, 471, 475 Radiography, 432, 471 Radioimmunoassay, 173, 471 Radiological, 148, 378, 461, 471 Raloxifene, 334, 471, 476 Randomized, 5, 6, 9, 11, 13, 17, 57, 64, 116, 126, 127, 151, 152, 172, 183, 254, 424, 471 Reabsorption, 438, 472 Reactive Oxygen Species, 32, 472 Reagent, 20, 428, 448, 472 Recombinant, 16, 33, 34, 63, 184, 209, 227, 242, 244, 252, 259, 266, 267, 285, 328, 472, 488 Recombinant Proteins, 285, 472 Recombination, 288, 472 Reconstitution, 61, 472 Rectum, 46, 406, 414, 421, 430, 431, 441, 445, 469, 472 Recurrence, 411, 472 Red blood cells, 218, 427, 436, 459, 466, 472, 475 Red Nucleus, 402, 472 Reductase, 168, 278, 396, 401, 472 Refer, 1, 236, 407, 414, 422, 425, 429, 448, 455, 472 Refraction, 472, 479 Regeneration, 81, 208, 259, 472 Regression Analysis, 45, 472 Relaxin, 252, 472 Remission, 260, 472, 473 Renin, 55, 121, 398, 408, 473 Renin-Angiotensin System, 408, 473 Reperfusion, 295, 454, 473 Reperfusion Injury, 295, 473 Respiration, 400, 408, 452, 473 Resting metabolic rate, 224, 473 Restoration, 24, 102, 454, 472, 473, 490 Retina, 42, 84, 412, 415, 421, 446, 458, 473, 474, 489

Index 507

Retinal, 43, 96, 134, 406, 421, 458, 473, 474 Retinal Neovascularization, 96, 134, 474 Retinal Vein, 474 Retinoblastoma, 354, 474 Retinoid, 29, 474 Retinol, 142, 473, 474 Retinopathy, 17, 190, 235, 249, 250, 263, 280, 290, 292, 295, 297, 373, 396, 420, 474 Retrospective, 179, 474 Retroviral vector, 34, 268, 474 Retrovirus, 34, 474 Reversion, 33, 474 Rhabdomyosarcoma, 154, 474 Rhamnose, 459, 474 Rheumatism, 151, 474 Rheumatoid, 84, 128, 414, 474 Rheumatoid arthritis, 84, 128, 414, 474 Ribonucleic acid, 150, 474 Ribose, 81, 394, 474 Ribosome, 474, 485 Rigidity, 460, 464, 474 Risk factor, 4, 8, 14, 38, 41, 45, 46, 57, 75, 77, 113, 146, 216, 220, 323, 372, 373, 448, 468, 474 Rod, 43, 403, 412, 474 Rod Outer Segments, 43, 474 Rodenticides, 462, 474 Rubber, 475 Rye, 179, 185, 331, 413, 427, 475 S Salicylate, 475 Salicylic, 475 Salicylic Acids, 475 Saline, 18, 475 Saliva, 471, 475 Salivary, 421, 460, 475, 481 Salivary glands, 421, 475 Sampling Studies, 51, 475 Saponins, 475, 480 Satellite, 125, 475 Satiation, 282, 475 Satiety Response, 151, 475 Saturated fat, 5, 283, 475 Scans, 27, 475 Schizophrenia, 121, 476 Sclerosis, 354, 401, 402, 414, 476 Screening, 46, 65, 217, 224, 239, 253, 282, 323, 364, 371, 413, 476 Secondary tumor, 451, 476 Secretory, 14, 15, 58, 59, 67, 86, 96, 100, 139, 206, 209, 211, 261, 265, 275, 476, 482

Sedentary, 76, 77, 149, 245, 247, 323, 473, 476 Segmental, 432, 476 Segregation, 472, 476 Seizures, 460, 476 Selective estrogen receptor modulator, 471, 476, 482 Selenium, 159, 163, 205, 258, 476 Self Care, 12, 303, 304, 476 Sella, 464, 476 Semen, 469, 476 Senescence, 39, 476 Senile, 269, 458, 476 Senile Plaques, 269, 476 Sensitization, 136, 216, 476 Sensor, 12, 89, 241, 442, 477 Septic, 296, 477 Sequence Homology, 461, 477 Sequencing, 40, 54, 477 Serine, 49, 55, 61, 62, 64, 70, 79, 91, 94, 102, 204, 253, 255, 296, 412, 425, 477, 486 Serologic, 440, 477 Serotonin, 209, 400, 413, 477, 486 Serous, 414, 425, 477 Serum Albumin, 259, 285, 286, 471, 477 Sex Characteristics, 394, 398, 470, 477, 482 Sex Determination, 354, 477 Sex Hormone-Binding Globulin, 127, 477 Shedding, 66, 477 Shivering, 477, 483 Shock, 97, 98, 133, 296, 312, 398, 438, 477, 486 Sibutramine, 151, 477 Side effect, 223, 239, 263, 264, 303, 316, 317, 339, 376, 395, 400, 405, 439, 477, 478, 484 Signs and Symptoms, 372, 373, 473, 478, 487 Skeletal, 21, 24, 27, 37, 40, 41, 44, 49, 52, 54, 61, 68, 70, 73, 75, 78, 85, 86, 87, 92, 120, 121, 125, 141, 145, 158, 160, 164, 178, 180, 184, 202, 205, 213, 216, 229, 234, 245, 248, 251, 258, 276, 277, 290, 298, 303, 323, 398, 412, 444, 453, 454, 478, 483 Skeleton, 393, 444, 468, 478 Skull, 418, 478, 482 Sleep apnea, 332, 478 Small intestine, 404, 410, 411, 412, 423, 437, 440, 443, 444, 454, 478, 486 Smooth muscle, 178, 323, 407, 408, 416, 469, 473, 478, 481 Sneezing, 462, 477, 478

508 Insulin

Social Environment, 471, 478 Sodium, 18, 176, 295, 396, 438, 472, 478, 481 Soft tissue, 406, 478 Solid tumor, 398, 478 Solvent, 256, 286, 404, 427, 433, 458, 462, 478 Somatic, 353, 394, 439, 452, 461, 479 Somatomedins, 243, 307, 308, 442, 479 Somatostatin, 18, 59, 96, 206, 457, 460, 479, 481 Somatotropin, 207, 479 Sorbitol, 396, 479 Sound wave, 479, 487 Soybean Oil, 466, 479 Spasmodic, 462, 479 Spatial disorientation, 422, 479 Specialist, 380, 421, 479 Specificity, 33, 63, 65, 68, 72, 79, 209, 251, 287, 395, 425, 479, 484 Spectrum, 14, 55, 367, 479 Sperm, 398, 412, 479, 486 Spinal cord, 406, 410, 412, 426, 450, 455, 461, 479, 481 Sporadic, 110, 466, 474, 479 Squamous, 182, 480 Stabilization, 256, 480 Staging, 475, 480 Steatosis, 429, 480 Steel, 304, 412, 480, 488 Stem Cells, 89, 258, 272, 480 Sterile, 368, 460, 480 Sterility, 110, 117, 152, 155, 441, 480 Steroid, 47, 51, 401, 404, 417, 433, 475, 480 Stimulant, 407, 444, 480 Stimulus, 173, 423, 463, 480, 483 Stomach, 58, 376, 393, 400, 403, 404, 421, 427, 431, 433, 437, 445, 454, 462, 478, 480 Strand, 465, 480 Stroke, 142, 216, 231, 234, 235, 237, 277, 346, 361, 363, 364, 366, 408, 409, 480 Stroke Volume, 408, 480 Stromal, 181, 480 Stromal Cells, 181, 480 Styrene, 475, 480 Subacute, 441, 480 Subarachnoid, 435, 480 Subclinical, 212, 441, 476, 480 Subcommissural Organ, 481 Submaxillary, 426, 481 Subspecies, 479, 481 Substance P, 228, 451, 472, 476, 481

Suction, 429, 481 Superoxide, 20, 60, 481 Superoxide Dismutase, 20, 481 Supplementation, 59, 119, 174, 176, 178, 181, 182, 183, 185, 481 Suppression, 25, 27, 32, 55, 66, 71, 76, 86, 90, 104, 172, 417, 481 Surfactant, 20, 428, 481 Suspensions, 242, 253, 481 Sweat, 439, 481 Sympathectomy, 24, 481 Sympathetic Nervous System, 481 Sympathomimetic, 422, 426, 444, 456, 481 Symphysis, 469, 481 Symptomatic, 37, 138, 148, 222, 460, 481 Synaptic, 456, 478, 482 Synaptic Transmission, 456, 482 Synergistic, 32, 291, 292, 468, 482 Systemic, 20, 68, 73, 138, 190, 239, 289, 293, 340, 341, 398, 399, 400, 405, 414, 426, 436, 441, 455, 465, 467, 482, 485, 486 Systemic lupus erythematosus, 399, 400, 414, 482 Systolic, 439, 482 T Tamoxifen, 123, 476, 482 Taurine, 198, 259, 404, 411, 482 Telangiectasia, 354, 482 Temporal, 26, 73, 435, 437, 482 Teratogenic, 27, 482 Teratoma, 412, 482 Terminator, 413, 482 Testicular, 206, 252, 401, 482 Testis, 398, 412, 427, 482 Testosterone, 29, 50, 72, 123, 174, 472, 477, 482 Tetany, 460, 482 Thalamic, 402, 483 Thalamic Diseases, 402, 483 Therapeutics, 74, 136, 140, 161, 165, 238, 259, 267, 272, 285, 342, 483 Thermogenesis, 276, 483 Thigh, 27, 483 Thinness, 320, 483 Third Ventricle, 401, 439, 481, 483 Thoracic, 114, 483, 490 Thorax, 393, 483 Threonine, 62, 64, 70, 73, 79, 91, 94, 102, 253, 461, 477, 483 Threshold, 439, 483 Thrombin, 255, 429, 465, 469, 470, 483 Thrombocytopenia, 465, 483

Index 509

Thromboembolism, 442, 483 Thrombolytic, 464, 483 Thrombomodulin, 469, 483 Thrombopenia, 400, 483 Thromboses, 400, 483 Thrombosis, 141, 152, 155, 183, 469, 480, 483 Thromboxanes, 283, 401, 424, 483 Thrombus, 417, 441, 453, 454, 465, 483 Thylakoids, 411, 484 Thymus, 198, 440, 448, 484 Thyroid, 245, 312, 460, 484, 487 Thyroid Gland, 460, 484 Thyroid Hormones, 312, 484, 487 Thyroxine, 396, 462, 484 Tissue Culture, 66, 484 Tissue Distribution, 70, 97, 484 Tissue Transplantation, 258, 484 Tolazamide, 280, 484 Tomography, 38, 449, 484 Tonicity, 444, 484 Tooth Preparation, 394, 484 Topical, 249, 427, 438, 462, 484 Torsion, 441, 484 Toxic, iv, 227, 277, 285, 402, 403, 404, 413, 419, 421, 426, 435, 440, 455, 456, 475, 476, 480, 484, 485 Toxicity, 20, 31, 32, 63, 71, 239, 255, 267, 408, 423, 484, 490 Toxicology, 348, 485 Toxins, 104, 399, 433, 441, 453, 485, 488 Toxoid, 80, 485 Trace element, 412, 485 Trachea, 406, 445, 449, 484, 485 Traction, 412, 485 Transcriptase, 474, 485 Transcription Factors, 36, 68, 69, 286, 485 Transcutaneous, 257, 485 Transduction, 22, 23, 24, 30, 31, 34, 39, 41, 43, 44, 49, 51, 58, 62, 63, 73, 78, 80, 87, 91, 92, 102, 160, 164, 186, 203, 204, 208, 281, 409, 442, 463, 478, 485 Transfection, 48, 66, 107, 113, 187, 261, 405, 485 Transfer Factor, 440, 485 Transferases, 434, 485 Transgenes, 37, 485 Translation, 103, 281, 485 Translational, 60, 63, 485 Transmitter, 393, 422, 450, 456, 485 Transplantation, 87, 112, 130, 220, 258, 259, 265, 268, 271, 412, 440, 445, 449, 485

Transport Vesicles, 44, 485 Trauma, 253, 454, 460, 486 Tremor, 460, 486 Tricuspid Atresia, 417, 486 Triglyceride, 6, 8, 21, 67, 79, 177, 210, 224, 238, 277, 282, 283, 323, 438, 439, 486 Troglitazone, 67, 71, 133, 152, 263, 269, 292, 319, 486 Trophoblast, 405, 486 Trypsin, 86, 267, 412, 426, 486 Tryptophan, 414, 477, 486 Tuberculosis, 416, 448, 475, 486 Tuberous Sclerosis, 354, 486 Tubulin, 452, 486 Tumor marker, 149, 405, 486 Tumor Necrosis Factor, 54, 72, 78, 81, 108, 111, 173, 486 Tumor suppressor gene, 154, 486 U Ubiquitin, 32, 455, 487 Ultralente Insulin, 9, 487 Ultrasonography, 38, 76, 432, 487 Ultrasound test, 222, 487 Unconscious, 398, 440, 487 Unit of Insulin, 246, 487 Uraemia, 460, 487 Urea, 122, 445, 481, 487 Uremia, 445, 487 Urethra, 469, 487 Uric, 439, 471, 487 Urinary, 238, 290, 312, 441, 457, 487, 490 Urine Testing, 304, 326, 487 Ursodeoxycholic Acid, 264, 487 Urticaria, 101, 397, 487 Uterus, 417, 419, 425, 450, 459, 467, 488 V Vaccination, 266, 488 Vaccine, 80, 218, 267, 285, 286, 394, 470, 488 Vacuole, 275, 488 Vagina, 420, 450, 488 Vaginal, 253, 488 Vanadium, 136, 169, 200, 488 Vascular endothelial growth factor, 145, 488 Vasculitis, 460, 488 Vasoconstriction, 427, 488 Vasodilatation, 229, 444, 488 Vasodilation, 29, 38, 47, 154, 160, 163, 228, 488 Vasodilator, 29, 406, 422, 454, 488 Vasomotor, 427, 488

510 Insulin

VE, 144, 216, 488 Vector, 34, 253, 259, 485, 488 Vegetative, 405, 488 Vein, 38, 217, 224, 398, 443, 456, 462, 474, 475, 488 Venoms, 419, 488 Venous, 148, 222, 400, 419, 469, 486, 488 Ventral, 401, 439, 488 Ventricle, 68, 402, 417, 437, 470, 482, 483, 486, 488, 489 Ventricular, 123, 130, 159, 163, 179, 417, 454, 486, 489 Ventricular Dysfunction, 159, 163, 489 Ventricular Function, 123, 489 Venules, 405, 408, 425, 451, 489 Vesicular, 41, 44, 105, 435, 489 Veterinarians, 245, 489 Veterinary Medicine, 347, 489 Vial, 317, 489 Vibrio, 285, 411, 489 Vibrio cholerae, 285, 411, 489 Vinblastine, 82, 172, 486, 489 Vinca Alkaloids, 489 Viral, 91, 237, 264, 266, 393, 408, 457, 471, 474, 485, 489 Virilism, 438, 489 Virulence, 402, 484, 489 Virus, 42, 134, 137, 259, 266, 286, 403, 408, 410, 426, 431, 434, 443, 464, 471, 474, 485, 489 Visceral, 27, 59, 115, 129, 137, 223, 234, 282, 323, 462, 489 Visceral fat, 27, 129, 489 Viscosity, 393, 489 Vitamin A, 442, 474, 489

Vitreous Body, 473, 489 Vitreous Hemorrhage, 421, 489 Vitro, 21, 24, 27, 33, 35, 41, 43, 49, 60, 70, 78, 133, 151, 154, 159, 163, 175, 181, 186, 204, 215, 242, 254, 258, 260, 262, 268, 436, 441, 484, 490 Vivo, 21, 22, 24, 25, 31, 35, 42, 43, 49, 60, 63, 71, 73, 74, 75, 77, 78, 94, 111, 119, 177, 180, 202, 211, 215, 244, 247, 248, 252, 253, 258, 260, 262, 279, 290, 436, 441, 451, 483, 490 W Waist circumference, 8, 323, 490 Weight Gain, 10, 17, 21, 155, 220, 224, 245, 288, 301, 317, 490 Weight Lifting, 230, 490 White blood cell, 393, 399, 414, 441, 446, 448, 449, 456, 464, 490 Whooping Cough, 462, 490 Windpipe, 484, 490 Wound Healing, 244, 490 X Xanthine, 75, 490 Xanthine Oxidase, 75, 490 Xenograft, 398, 490 X-ray, 64, 104, 222, 224, 287, 401, 415, 430, 449, 456, 475, 490 Y Yeasts, 430, 462, 490 Z Zearalenone, 186, 490 Zoonoses, 471, 490 Zygote, 415, 490 Zymogen, 412, 469, 490

Index 511

512 Insulin

Insulin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Insulin Resistance - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Insulin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Insulin Resistance - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Recommend Documents