Nutrition and Diabetes: Pathophysiology and Management

NUTRITION and DIABETES Pathophysiology and Management

NUTRITION and DIABETES Pathophysiology and Management Edited by

EMMANUEL OPARA

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Foreword Diabetes mellitus is increasing in frequency worldwide; there is even talk of its reaching epidemic proportions. No one doubts that this has something to do with changes in diet and methods of food preparation — but exactly what and how is disputed, sometimes quite acrimoniously. The dispute is not new, however, and has been raging ever since Thomas Willis wrote in 1697, “diabetes was so rare among the ancients that many famous physicians made no mention of it and Galen knew only two sick of it. But in our age given to good fellowship and gushing down chiefly unalloyed wine, we meet with examples and instances enough, I may say daily, of this disease.” He clearly implicated changes in eating habits and lifestyle in what he perceived was an increasing incidence of what we would now call type 2 diabetes. So, what is new? Is it the ease of making a diagnosis and changing the diagnostic criteria, and our increasing awareness of it, ageing of the population, changes in lifestyle, especially as regards exercise and the availability of plentiful food, or, as seems increasingly likely, a combination of all of them? The increasing incidence of diabetes is not confined to any particular country or to either of the two common types of illness, which, though sharing a final common path, have such different origins. The rate of increase is faster in older people, with presumed type 2, than in children and adolescents with presumed type 1 diabetes, as was already apparent from epidemiological studies of the incidence of diabetes in New York as long as 80 years ago. The increase in diabetes is, at least in part, attributable to an even more rapid increase in the prevalence of obesity. Nevertheless there is a well-established increase in the incidence of type 1 diabetes along with that of many other autoimmune diseases and it is almost certainly associated with changes in the environment and eating habits, but not with obesity. The special role of nutrition in the management of diabetes was recognized long before the era of modern scientific medicine, but it is only within the past century that it has been firmly linked to pathogenesis. Differentiation of diabetes into two main and many subordinate types is comparatively recent, and, while suspected on clinical grounds, was only established, like so many advances in medical knowledge, by major changes in technology. Some of these, such as the use of respiratory quotients to unravel the complexities of metabolism in health and disease, have almost vanished undeservedly from the investigative armamentarium. Others, such as molecular genetics, have still to fulfill their potential. Meanwhile, diabetologists and nutritionists must depend upon advances made possible by the application of nutritional biochemistry, epidemiology, and laboratory medicine, most notably in the measurement of hormones and neurotransmitters by immunoassay, to improve their understanding and management of this increasingly important syndrome.

This book examines all aspects of the relationship between nutritional status and the pathogenesis, diagnosis, and treatment of patients with the various illnesses that manifest themselves as diabetes. It will be of especial value to medical practitioners and dieticians giving day-to-day care to the growing number of patients at both ends of the age spectrum, as well as to those in the middle. Epidemiologists and directors of public health policy will also find in it much to interest them, as will laboratory scientists concerned with unraveling the complex interactions between us and our food. The seminal discovery that diabetes, referred to by Willis as the pissing disease because of its most prominent symptom, was associated with an abnormality of sugar metabolism led many early investigators to direct their attention to carbohydrates in the diet to the exclusion of other constituents. This has gradually, but still not completely, changed with recognition that most types of diabetes are but one manifestation of a more general disturbance of metabolism in which fats, and, to a lesser extent, proteins, are equally or more profoundly affected. The rediscovery of the endocrine role of the gastrointestinal tract in determining the fate and disposal of ingested food has been complemented, in more recent times, by recognition of the role of the gut in regulating appetite through its ability to release neurotransmitters such as Ghrelin and peptide PPY. Together, these make the plea, constantly heard from the obese in the past, that their condition was “all due to my gland’s doctor” no longer dismissible as complete nonsense. Important as endocrine factors are in the pathogenesis of diabetes, it is impossible to deny the role of genetic, environmental, sociological, and even commercial factors in its genesis. The relevance of antenatal, and possibly prenatal, nutrition of the child’s mother in determining its metabolic fate and later development of obesity, hypertension, and other features of the metabolic syndrome was highlighted by the epidemiological studies of David Barker, who painstakingly scrutinized the obstetric records of large cohorts of patients and their appropriate controls in the United Kingdom (U.K.). His conclusions have subsequently been confirmed by Nick Hales in experiments on laboratory animals, and explain, at least in part, the observed worldwide increase in the metabolic syndrome and all its manifestations, including type 2 diabetes. Incrimination of specific items of diet — notably refined sugars, including highfructose corn syrups and saturated fats — especially when combined in what are disparagingly described as junk foods — and by more temperate commentators as energy-dense foods — is even more contentious today than it was more than half a century ago. So, too, is the importance of the glycemic index, which, though relevant to individual foods, rarely applies to mixed meals. The importance of dietary fiber in determining the bioavailability of absorbable carbohydrates in the diet is undeniable, but whether this is due to their chemical or physical characteristics, or a combination of both, is a moot point, as are generalizations drawn from selected geographical epidemiological studies. Difference in the glycemic index of foods depends as much upon their physical form — whole versus ground brown rice, for example — as upon their chemical composition and brings into question much of the value of what is often described as nutritional labeling. Methods of food preparation and storage that alter the nature

and amount of protein glycated prior to ingestion, though long recognized as important by food scientists, has received scant attention from diabetologists and nutritionists in the past. This may be expected to change with the demonstration that ingested, glycated proteins have a detrimental effect upon the body akin to that produced by glycation in vivo and which is held to be responsible for many of the adverse effects of chronic hyperglycemia. It is impossible to overemphasize the importance of micronutrients in the pathogenesis of disease. This has been recognized ever since the link between vitamin C deficiency and scurvy was first established more than two centuries ago. Nevertheless, despite many claims made for them, evidence that incriminates micronutrients in the pathogenesis of the common forms of diabetes and for their use in prevention and treatment is far from clear. None of them yet has a definite role. Meanwhile, other nonessential constituents of the diet, such as coffee and alcoholic drinks, that have attracted opprobrium or downright condemnation by those seeking to demonstrate a link between their habitual consumption and the pathogenesis of diabetes have undergone radical revision or reversal. Large-scale, prospective epidemiological studies have revealed, contrary to expectations, their possibly beneficial rather than detrimental effect when used appropriately within the diet. How much this is due to their antioxidant content and how much to their pharmacologically active constituents is unsettled, but illustrates the importance of establishing a firm data base before proffering nutritional advice, which has been all too rare in the past. There clearly is no simple, one-stop solution to the role of nutrition in general, and of food and drink in particular, in the pathogenesis of diabetes and obesity — as many politicians and their nutritionist gurus would have us believe. Science is the growth of knowledge based upon evidence, and readers will find within the pages that follow the evidence upon which to base answers to many of the questions posed by the rising incidence of diabetes and obesity in the modern world. They will, more importantly, also find pointers to gaps in our knowledge and areas of ignorance that have hitherto been glossed over, ignored, or just not considered, but which will, in all probability, yield to further investigation. Vincent Marks Emeritus Professor of Clinical Biochemistry University of Surrey Guildford, Surrey, U.K.

Preface Diabetes and obesity are two common disorders that have come to be appropriately recognized as enormous burdens both to the afflicted individuals, their countries, and the modern society in general. What is most striking is the relationship between obesity and impaired glucose regulation that predominantly results in overt diabetes. Consequently, as the incidence of obesity has risen in virtually every population, so has the prevalence of type 2 diabetes. Perhaps more alarming is the trend of increased incidence of obesity and type 2 diabetes among children. When one considers that both disorders are by nature chronic and tend to be associated with a host of complications, it becomes quite obvious how they can become the bane of today’s world. The purpose of Nutrition and Diabetes: Pathophysiology and Management is to provide a unique forum that highlights the link between the problems of obesity and diabetes, albeit various aspects of each disorder are separately discussed in different sections of the book. However, the interrelationships of the various areas of the disease processes become quite apparent in the many overlaps among the contents of many topics covered in this book. Enormous efforts have been made by the different contributors in each section of the book to first provide an overview of each topic, then discuss the mechanistic aspects of the given problem, and to finally link the pathophysiological processes to the treatment. The book is divided into three sections: Pathophysiology and Treatment of Obesity; Pathophysiology and Treatment of Diabetes; and The Role of Oxidative Stress in the Pathogenesis and Treatment of Diabetic Complications. Each section begins with an introduction. Nutrition and Diabetes: Pathophysiology and Management is intended to be a reference handbook for physicians, nutritionists, and other health-care workers who deal daily with the various problems associated with obesity and diabetes. Researchers who need to see the gaps that still need to be filled in our understanding of the disease processes, as well as strategies for drug development for effective management of the problems, will find the book to be of significant interest. The book should also be of significant interest to public-policy makers involved in formulating health policies, especially in developing countries. Finally, by reading this book, individual subjects afflicted with either obesity or diabetes or both would learn a lot about how to help themselves and about understanding the basis of the treatment provided by their health-care team. I would like to express my sincere gratitude to a lot of people who have helped in my career in different ways. First, I would like to thank all my former teachers, particularly Professor Vincent Marks and John E. Gerich, M.D., who inspired in me the love of metabolic and diabetes research at the University of Surrey and the Mayo Clinic, respectively. I am also greatly indebted to Vay Liang W. Go, M.D., presently of the University of California Los Angeles, for giving me the opportunity to work

with him at the National Institutes of Health, Bethesda, Maryland, and for his continued mentorship in my academic career. Secondly, I would like to express my gratitude to all my former students and fellows at Duke University, Durham, North Carolina, who have helped to shape my career by making seminal contributions to my research. Some of these former trainees of mine, such as Dr. Marc Garfinkel, director of islet transplantation at the University of Chicago, and Dr. William Kendall of the Duke University Medical Center, who are now among my best friends, deserve special mention. I am also particularly grateful to another one, Marcus Darrabie, currently a medical student at Duke, who helped with the illustrations used in my chapters in this book. Finally, I would like to acknowledge the great patience, personal sacrifice, and unqualified support of my wife, Clarice, and our four children, Ogechi, Chiedu, Chucky, and Ike. I am eternally grateful to them for giving me the luxury of extended periods of time away from home in my career and during the preparation of this book. I wish to dedicate this book to my parents, Eugene and Caroline (deceased), for their sacrifices in providing me a most rewarding education that prepared me for an academic career and for their love and support for what I do.

Editor Emmanuel C. Opara, Ph.D., is a research professor and co-director, Engineering Center for Diabetes Research and Education at the Pritzker Institute of Medical Engineering, Illinois Institute of Technology, Chicago, and a senior investigator at the University of Chicago Human Islet Transplant Program. He was previously a member of faculty of the Duke University School of Medicine in Durham, North Carolina (1988–03), a visiting fellow at the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, Maryland (1986–88), and a World Health Organization (WHO) Fellow in endocrinology/metabolism at the Mayo Clinic, Rochester, Minnesota (1984–86). Dr. Opara’s main research focus is diabetes, and he has worked in many areas of diabetes research for more than 20 years. Currently, he is mainly working on developing a bioartificial pancreas using the approach of islet cell microencapsulation. He also studies the role of oxidative stress in the pathogenesis and progression of diabetes and digestive disease. His other research interests include the role of nutritional factors in the etiology and management of diabetes. He has about 200 publications of original articles, abstracts reviews, and book chapters on these subjects. Dr. Opara is a member of many professional organizations, including: American Diabetes Association, American Federation for Medical Research, American Pancreatic Association, American Gastroenterological Association, Society for Black Academic Surgeons, Transplantation Society, and International Pancreas and Islet Transplantation Association.

Contributors Tan Attila, M.D. Division of Gastroenterology & Hepatology Medical College of Wisconsin Milwaukee, Wisconsin Connie W. Bales, Ph.D., R.D. Center for Aging Duke University Medical Center Durham, North Carolina Jarol Boan, M.D., M.P.H. Associate Professor of Medicine Penn State College of Medicine Hershey Medical Center Hershey, Pennsylvania Ali Cinar, Ph.D. Department of Chemical Environmental Engineering Illinois Institute of Technology Chicago, Illinois Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Department of Medicine & General Clinical Research Center The University of Tennessee Health Science Center Memphis, Tennessee G. Lynis Dohm, Ph.D. Departments of Physiology, Internal Medicine, and Pediatrics East Carolina University Greenville, North Carolina

Fateh Entabi, M.D. Department of Surgery Massachusetts General Hospital Boston, MA Mark N. Feinglos, M.D., C.M. Division of Endocrinology, Metabolism, and Nutrition Department of Medicine Duke University Durham, North Carolina Michael Freemark, M.D. Division of Pediatric Endocrinology and Diabetes Duke University Medical Center Durham, North Carolina Leonid E. Fridlyand, Ph.D. Department of Medicine University of Chicago Chicago, Illinois Roger Harms, M.D. Department of Obstetrics & Gynecology Mayo Clinic Rochester, Minnesota Robert D. Hoeldtke, M.D., Ph.D. Department of Medicine West Virginia University School of Medicine Morgantown, West Virginia

Alexander J. Kaminsky, M.D. University of Michigan Department of Neurology Ann Arbor Veterans Administrative Medical Center Ann Arbor, Michigan William F. Kendall, Jr., M.D. Department of Surgery Duke University Medical Center Durham, North Carolina Timothy R. Koch, M.D. Washington Hospital Center Section of Gastroenterology Washington, D.C. William E. Kraus, M.D. Division of Cardiology Department of Medicine Duke University Medical Center Durham, North Carolina Lillian F. Lien, M.D. Division of Endocrinology, Metabolism, and Nutrition Department of Medicine Duke University Durham, North Carolina Jean Claude Mbanya, M.D., M. Phil., Ph.D. Endocrine and Diabetes Unit Development of Internal Medicine & Specialties Faculty of Medicine and Biomedical Sciences University of Yaoundé 1 Yaoundé, Cameroon Ross L. McMahon, M.D., F.R.C.S.C., FACS Weight Loss Surgery Center Duke University Medical Center Durham, North Carolina

Linda M. Morgan, Ph.D. School of Biomedical and Molecular Sciences University of Surrey Guildford, United Kingdom Emmanuel C. Opara, Ph.D. Pritzker Institute of Biomedical Science & Engineering Illinois Institute of Technology Chicago, Illinois Louis H. Philipson, M.D., Ph.D. Department of Medicine University of Chicago Chicago, Illinois Jama L. Purser, P.T., Ph.D. Center for Aging Duke University Medical Center Durham, North Carolina James W. Russell, M.D., M.S., F.R.C.P. Department of Neurology University of Michigan Ann Arbor Veterans Administrative Medical Center Ann Arbor, Michigan Cris A. Slentz, Ph.D. Division of Cardiology Department of Medicine Duke University Medical Center Durham, North Carolina Eugene Sobngwi, M.D., M. Phil., Ph.D. Department of Endocrinology and Diabetes and Clinical Investigation Centre Saint-Louis University Paris, France

John P. Thyfault, Ph.D. Department of Physiology Brody School of Medicine East Carolina University Greenville, North Carolina Michael T. Watkins, M.D. Harvard Medical School Massachusetts General Hospital Division of Vascular Surgery Boston, MA

Carlton J. Young, M.D. University of Alabama Birmingham, AL

Table of Contents SECTION I

Pathophysiology and Treatment of Obesity

Introduction................................................................................................................3 Chapter 1 Neuroendocrine Regulation of Food Intake..............................................................5 Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Chapter 2 The Enteroinsular Axis ............................................................................................27 Linda M. Morgan, Ph.D. Chapter 3 Achieving a Healthy Body Weight: Diet and Exercise Interventions for Type 2 Diabetes .................................................................................................43 Connie W. Bales, Ph.D., R.D., and Jama L. Purser, P.T., Ph.D. Chapter 4 Metabolic Syndrome: Recognition, Etiology, and Physical Fitness as a Component............................................................................................................57 William E. Kraus, M.D. and Cris A. Slentz, Ph.D. Chapter 5 Metabolic Alterations in Muscle Associated with Obesity ....................................79 John P. Thyfault, Ph.D. and G. Lynis Dohm, Ph.D. Chapter 6 Nonsurgical Management of Obesity......................................................................99 Jarol Boan, M.D., M.P.H. Chapter 7 Bariatric Surgery for Obesity ................................................................................111 Ross L. McMahon, M.D., F.R.C.S.C., FACS

Chapter 8 Postoperative Management of the Bariatric-Surgery Patient................................125 Jarol Boan, M.D., M.P.H.

SECTION II

Pathophysiology and Treatment of Diabetes

Introduction............................................................................................................137 Chapter 9 Epidemiology, Risks, and Health-Care Expenditures for Diabetes and Its Complications ...................................................................................................139 William F. Kendall, Jr., M.D. Chapter 10 Nutrient Interactions and Glucose Homeostasis ...................................................161 Emmanuel C. Opara, Ph.D. Chapter 11 Type 2 Diabetes in Childhood: Diagnosis, Pathogenesis, Prevention, and Treatment ........................................................................................................177 Michael Freemark, M.D. Chapter 12 Management of Obesity-Associated Type 2 Diabetes ..........................................205 Lillian F. Lien, M.D., and Mark N. Feinglos, M.D., C.M. Chapter 13 Management of Type 2 Diabetes in Underrepresented Minorities in the U.S. ..................................................................................................................227 Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Chapter 14 Management of Diabetes in Developing Countries..............................................249 Jean Claude Mbanya, M.D., M. Phil., Ph.D. and Eugene Sobngwi, M.D., M. Phil., Ph.D. Chapter 15 Diabetes in Pregnancy ...........................................................................................267 Roger Harms, M.D.

Chapter 16 Web-Based Simulations for Dynamic Variations in Blood-Glucose Concentration of Patients with Type 1 Diabetes ..................................................281 Ali Cinar, Ph.D.

SECTION III

The Role of Oxidative Stress in the Pathogenesis and Treatment of Diabetes and Its Complications

Introduction............................................................................................................301 Chapter 17 The Nutrient Paradox: Oxidative Stress in Pancreatic β-Cells ............................303 Leonid E. Fridlyand, Ph.D. and Louis H. Philipson, M.D., Ph.D. Chapter 18 Oxidative Stress in Type 1 Diabetes: A Clinical Perspective...............................319 Robert D. Hoeldtke, M.D., Ph.D. Chapter 19 Oxidative Stress and Glycemic Control in Type 2 Diabetes................................345 Emmanuel C. Opara, Ph.D. Chapter 20 Oxidative Stress and Vascular Complications of Diabetes Mellitus ....................361 Fateh Entabi, M.D. and Michael T. Watkins, M.D. Chapter 21 Oxidative Injury in Diabetic Neuropathy..............................................................381 James W. Russell, M.D., M.Sc. and Alexander J. Kaminsky, M.D. Chapter 22 Diabetic Nephropathy............................................................................................399 Carlton J. Young, M.D. Chapter 23 Pathophysiology and Management of Diabetic Gastropathy ...............................427 Tan Attila, M.D. and Timothy R. Koch, M.D. Index ......................................................................................................................449

Section I Pathophysiology and Treatment of Obesity

Introduction For more than two decades, there has been an exponential increase in the incidence of obesity around the world. This trend has been more apparent in the United States of America where the incidence of obesity in adults has more than doubled over that period. With this uncontrolled rise in obesity has been a concomitant increase in the diseases associated with obesity, such as type 2 diabetes, hypertension, and cardiovascular disease. It is perhaps more disturbing to note that over this same period, there has even been a higher increase in the prevalence of obesity in the American pediatric community. Not surprisingly, we have also seen an unprecedented increase in the number of diagnosed cases of type 2 diabetes in children and adolescents. It is therefore most timely to have different aspects of this problem addressed by reputable experts who routinely deal with it. Thus, this section is focused on the disease obesity, which is defined as an excess of body fat, which increases body weight beyond physical and skeletal requirements. It is well-established that a delicate balance between energy intake and expenditure is required to maintain a healthy body weight. Certainly, the amount of energy intake depends both on the quantity and quality of food consumed. On the other hand, energy expenditure is critically dependent upon the basal metabolic rate, the thermic effect of food, and mandatory and volitional physical activity. Although many factors affect food consumption, it is very clear that appetite and satiety, which are regulated by neuroendocrine factors, play a key role, as is efficiently reviewed in this section. The role of the factors released from the canal through which food is consumed and processed, prior to utilization by various tissues, is also important in regulating the fate of the nutrients. Obviously, obesity is the result of an imbalance between food intake and disposal, and it is a consequence of the failure of one or more factors involved in any of the two processes. Once a primary cause of the failure is recognized, it is required that appropriate steps first be taken to try and correct the problem. In most cases, returning an overweight individual to normal weight through reversal of the failed processes of maintaining a normal body weight does not achieve the desired objective by conventional treatment, and extraordinary measures, such as surgery, become unavoidable, as outlined in this section. Unfortunately, adoption of a drastic procedure to treat obesity, such as surgery, comes at price to the patient. There are also key issues required in routine management of such patients. These issues and the other chronic complications of obesity, such as the metabolic syndrome, insulin resistance, and type 2 diabetes, are also addressed in this section.

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1

Neuroendocrine Regulation of Food Intake Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P.

CONTENTS I. Introduction....................................................................................................6 II. Appetite and Satiety ......................................................................................6 III. Central Nervous System Localization of Feeding Control...........................7 A. Hypothalamus and Brain Stem .............................................................7 IV. Hypothalamic Neuropeptides That Stimulate Food Intake...........................7 A. Neuropeptide Y......................................................................................7 B. Agouti-Related Protein..........................................................................8 C. Hypocretins/Orexins..............................................................................8 V. Anorexigenic Neuropeptides .........................................................................9 A. Melanocortins ........................................................................................9 B. Cocaine- and Amphetamine-Regulated Transcript ...............................9 C. Serotonin..............................................................................................10 VI. Peripheral Signals in the Regulation of Food Intake..................................10 A. Adipocyte-Derived Signals .................................................................11 B. Adipocytokines....................................................................................11 C. Leptin...................................................................................................11 1. Mechanism of Leptin Action ........................................................12 2. Leptin and Insulin Action .............................................................12 3. Exogenous Leptin Therapy for Human Obesity...........................14 VII. Pancreatic Signals........................................................................................14 A. Insulin ..................................................................................................14 B. Pancreatic Polypeptide ........................................................................15 VIII. Gastrointestinal Peptides .............................................................................16 A. Ghrelin.................................................................................................16 B. Peptide YY ..........................................................................................17 C. Glucagon-Like Peptide-1 ....................................................................17 D. Cholecystokinin ...................................................................................18 IX. Conclusions..................................................................................................18 5

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Nutrition and Diabetes: Pathophysiology and Management

Acknowledgments....................................................................................................19 References................................................................................................................19

I. INTRODUCTION Regulation of energy homeostasis is critical to the survival of any species. Therefore, intricate behavioral, metabolic, and neuroendocrine mechanisms have evolved to integrate energy intake and dissipation. A delicate balance between intake and expenditure of energy is required to maintain healthy weight. Perhaps for teleological reasons, the mechanisms that regulate energy homeostasis are biased in favor of net positive energy and are geared toward defense of weight loss rather than prevention of obesity. Hence, spontaneous weight loss in the absence of disease is rare and the experience of progressive weight gain in free-living humans is common. The adaptations that defend against weight loss eventually become maladaptive when obesity and its related metabolic and cardiovascular complications supervene, as in the present era (1, 2). At its core, obesity signifies chronic disequilibrium between food consumption and energy expenditure. Total energy expenditure (TEE) comprises basal or resting energy expenditure (REE), thermic effect of food (TEF), mandatory physical activities of daily living (ADL), and volitional physical activity or exercise (3). The contributions of TEF and ADL to TEE are rather modest, and the rate of voluntary physical activity is universally low among modern humans, leaving REE the energy-expenditure mode of choice for most people. The REE declines with age, which explains the tendency of positive energy balance and obesity in older persons. The TEE also is correlated positively with body surface area and is higher in obese than lean individuals. However, the REE compensation for obesity is ineffective in inducing weight loss or restoring normal weight. Therefore, REE, the major component of energy expenditure for most sedentary persons, is a practically nonmodifiable factor in energy homeostasis. This leaves restriction of food intake and volitional exercise as the main strategies for effective weight control.

II. APPETITE AND SATIETY The “afferent” limb of the energy homeostasis loop is food consumption. Food intake is driven by appetite and terminated by satiety. Hunger is the physiological response to appetite, whereas meal termination occurs in response to satiety signals. The exact mechanisms controlling the primal instincts of appetite and hunger are not understood precisely. It is known, however, that a host of behavioral, environmental, cognitive, and situational influences can modify responses to hunger. Thus, appetite triggers hunger, but the latter can be overridden or suppressed to enable delay of food intake to a more appropriate time. Similarly, several organic and psychiatric disorders are associated with perturbation of appetite. The present review focuses on the neurohormonal regulation of food intake, and attempts to integrate seminal experimental findings in rodents with current and future directions in human metabolic research and antiobesity drug development.

Neuroendocrine Regulation of Food Intake

7

III. CENTRAL NERVOUS SYSTEM LOCALIZATION OF FEEDING CONTROL A. HYPOTHALAMUS

AND

BRAIN STEM

The hypothalamus integrates diverse signals, including brain neurotransmitters, peripheral neurohumoral afferents, adipocyte-derived signals, gastrointestinal peptides, and other afferent inputs, to regulate energy homeostasis. The arcuate nucleus (ARC) at the base of the hypothalamus expresses receptors for hormones and neuropeptides that regulate feeding. The paraventricular nucleus (PVN) in the anterior hypothalamus, the major site of corticotropin releasing hormone (CRH) and Thyroid Releasing Hormone (TRH) secretion, receives rich projections from the ARC. Thus, the PVN integrates diverse paracrine and endocrine metabolic signals with classical neuroendocrine pathways mediated through the thyroid and hypothalamic-pituitary-adrenal axes. Following ingestion of a meal, vagal afferent projections to the brain stem provide satiety signals (4). Neuronal projections from the nucleus tractus solitarius to the PVN and lateral hypothalamus link the brain stem with the hypothalamus. These projections include GLP-1 and serotoninergic neurons. Studies in decerebrate rats, in which the brain stem and the forebrain are disconnected, show a critical role of the brain stem in control of meal size (5).

IV. HYPOTHALAMIC NEUROPEPTIDES THAT STIMULATE FOOD INTAKE The hypothalamic orexigenic signals include neuropeptide Y (NPY), agouti-related protein (AgRP), and the hypocretins/orexins.

A. NEUROPEPTIDE Y NPY, a 36-amino-acid, COOH-terminally amidated polypeptide first isolated from porcine brain, has structural analogy with peptide YY and pancreatic polypeptide (6). NPY rapidly stimulates food intake following intracerebroventricular (i.c.v.) injection in rodents. The appetite-stimulating effects of NPY lead to sustained hyperphagia and weight gain in mice receiving chronic i.c.v. administration. The specificity of NPY’s effect has been established in studies that employed coadministration NPY antagonists or its antibodies, both of which inhibited food intake in rats (7). The role of NPY as a central physiological trigger of meal initiation is suggested by studies showing a rapid increase in hypothalamic NPY expression in the PVN before meal times and persistence of NPY gene expression throughout the period of enforced hunger. The orexigenic action of NPY is mediated by interaction with Y1 and Y5 receptors (8). Interestingly, NPY expression in the arcuate nucleus is potently antagonized by the anorexigenic hormone leptin. Furthermore, activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Central administration of PYY3-36 (a Y2 receptor agonist secreted by intestinal endocrine L cells) into the

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Nutrition and Diabetes: Pathophysiology and Management

arcuate elicits a marked inhibition of food intake. Also, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (9). Thus, NPY antagonism appears to be a rather promising potential strategy for antiobesity drug development. The location of the median eminence outside the blood-brain barrier suggests that novel compounds that inhibit NPY gene expression, secretion, or interaction with Y1 and Y5 receptors could possibly be delivered to the hypothalamus when administered systemically.

B. AGOUTI-RELATED PROTEIN AgRP is expressed exclusively in the arcuate nucleus of the hypothalamus and colocalizes to the same neurons that secrete NPY (10). Several reports have confirmed the status of AgRP as a potent orexigenic factor: A single i.c.v. injection of AgRP increases food intake for several days in rodents (11). In contrast to the shortlived effect of NPY, chronic treatment with AgRP leads to sustained hyperphagia and obesity (12). The orexigenic effect of AgRP is mediated through antagonism of MC3 and MC4 receptors. Such antagonism effectively reverses the inhibition of food intake induced by alpha-MSH. The arcuate neurones that cosecrete NPY/AgRP are potently inhibited by leptin and insulin, and activated by ghrelin (8, 13).

C. HYPOCRETINS/OREXINS The hypothalamic peptides hypocretin-1 and hypocretin-2 were discovered in 1998 by subtractive polymerase chain reaction (14). In the same year, homologous hypothalamic peptides named orexins 1 and 2 were discovered by Sakurai et al. (15) and were shown to potently stimulate food intake in rats (15). The hypocretins/orexins stimulate food intake in rodents, an effect that is blocked by neutralizing antibodies to endogenous hypocretins (17). In addition to directly stimulating food intake, the hypocretins/orexins may also influence energy homeostasis in other ways. For example, hypocretin levels increase in response to exercise, neuroglycopenia, and enforced wakefulness (16). Hypocretin-secreting neurons localize exclusively to the lateral hypothalamus, the region of the brain long known to integrate appetite signals. Although intriguing as modulators of food intake, interest in the hypocretins/orexins shifted to their role in sleep regulation when the genes for hypocretins/orexins were found to be the loci for narcolepsy (18, 19). Documented mutations in the human hypocretin/orexin genes are rare among patients with sleep disorders, but nearly 90 percent of patients with narcolepsy-cataplexy have subnormal cerebrospinal fluid hypocretin levels (20). The latter finding is inconsistent with a primary orexigenic role of the hypocretins/orexins as the mechanism for the increased prevalence of obesity, insulin resistance, and type 2 diabetes among patients with narcolepsy (Nishino 2001b). These metabolic disorders are more likely the result of the physical hypoactivity associated with narcolepsy. It must be noted, however, that the hypocretin/orexin system functions centrally as the major integrator of excitatory impulses from monoaminergic (dopamine, norepinephrine, serotonin, histamine) and cholinergic fibers that maintain wakefulness and vigilance (21). Thus, besides a direct orexigenic effect, the

Neuroendocrine Regulation of Food Intake

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hypocretins/orexins could exert metabolic effects through modulation of central autonomic outflow. However, the hypocretins/orexins are less attractive candidates for drug development because their reported effects on food intake are less robust and consistent compared with the orexigenic effects of NPY.

V. ANOREXIGENIC NEUROPEPTIDES As a central integrator of energy homeostasis, the hypothalamus also is a source of neuropeptides that inhibit food intake or induce satiety. The hypothalamic anorexigenic agents include the melanocortins, cocaine- and amphetamine-regulated transcript (CART), and serotonin.

A. MELANOCORTINS The melanocortins are derived from site-specific, posttranslational cleavage of the precursor parent molecule proopiomelanocortin (POMC). Cleavage of POMC within the anterior pituitary gives rise to Adrenocorticotrophic hormone (ACTH), which acts through the MC2 receptor to stimulate adrenal steroidogenesis. Elsewhere in the brain, POMC is cleaved to another melanocortin, alpha-MSH, which is an agonist for the MC3 and MC4 receptors. Administration of alpha-MSH (i.c.v.) in rodents results in weight loss through inhibition of food intake and stimulation of energy expenditure (22). These actions are mediated through activation of two neuronal melanocortin receptor subtypes (MC3r and MC4r) and antagonized by an adjacent subset of hypothalamic neurons that express AgRP and NPY. The NPY/AgRP neurons that inhibit MC3r and MC4r are themselves inhibited by leptin and insulin. The integrated physiology of the interactions of these opposing neuropeptides is evident from their weight-related alterations. Following weight loss, the deceasing levels of insulin and leptin lead to activation of NPY/AgRP neurons and inhibition of POMC neurons (23). These counterregulatory changes induce accelerated food intake and accumulation of fat. Defects along the melanocortin signaling pathway, such as those seen in transgenic mice with targeted disruption of the MC4 receptor (knock-outs), result in hyperphagic and massive obesity (24). Recently, fairly widespread functional mutations of the human MC4 receptor have been demonstrated in patients with severe childhood obesity (25) and also linked to binge-eating disorder (26). It should be noted, however, that the majority of obese patients have no demonstrable mutations in MC4, yet such persons may possibly benefit from future therapies targeting activation of MC4 pathways. Indeed, intransal administration of a melanocortin fragment (MSH/ACTH 4-10) looks promising in that regard by inducing modest weight loss (27).

B. COCAINE-

AND

AMPHETAMINE-REGULATED TRANSCRIPT

Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the brain, especially in the hypothalamic nuclei and in the anterior pituitary. Within the arcuate nucleus, POMC colocalizes to neurons that also express CART. Injection of CART (1–100 pmol, i.c.v.) resulted in dose-dependent inhibition of food intake in

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rats. The effect was observed within 20 minutes and lasted approximately four hours. The decrease in food intake following treatment with CART was accompanied by inhibition of gastric emptying and reduction of oxygen consumption. The arcuate POMC/CART neurons act as downstream effectors of the anorexigenic action of leptin and are markedly stimulated by i.c.v. injection of leptin (28). Interactions between CART and the endogenous opioid, serotononergic (29), and cannabinoid (30) systems provide additional mechanisms for the anorexigenic effects of CART.

C. SEROTONIN The amino acid derivative 5-hydroxytryptamine (serotonin, 5-HT) has ubiquitous neurotransmitter functions on numerous central nervous system (CNS) targets (31). Receptors for 5-HT are widely expressed in regions, including the limbic system, Raphe nucleus, and the hypothalamus. Activation of 5-HT receptors (especially the 5-HT2C subtype) is associated with inhibition of food intake. A similar anorexigenic effect is observed following augmentation of serotonin abundance through inhibition of its reuptake. Studies in rodents have shown that deletion of the serotonin 5-HT2C gene results in marked hyperphagia (32). Unfortunately, clinical experience with selective serotonin reuptake inhibitors shows only modest and inconsistent effects on body weight, indicating that the serotoninergic pathway is overridden by more powerful orexigenic impulses under normal physiological conditions. The major central neuropeptides that impact food intake are summarized in Table 1.1.

VI. PERIPHERAL SIGNALS IN THE REGULATION OF FOOD INTAKE The peripheral hormones that regulate food intake include several gastrointestinal, pancreatic, and adipocyte-derived peptides (Table 1.2). Based on extensive studies in rodents and limited human data, these peptides can be classified as having orexigenic (e.g., ghrelin) or anorexigenic (e.g., insulin, peptide YY, glucagon-like polypeptide, cholecystokinin, leptin) effects.

TABLE 1.1 Selected Central Neuropeptides that Modulate of Food Intake Orexigenic

Anorexigenic

Neuropeptide Y Agouti-related protein Orexins a Orexin b

alpha-Melanocyte stimulating hormone Corticotropin-releasing hormone Cocaine-amphetamine regulated transcript Serotonin

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TABLE 1.2 Selected Peripheral Modulators of Food Intake Signal

Main Targets

Anorexigenic Leptin Hypothalamus Peptide YY Hypothalamus Pancreatic polypeptide Hypothalamus Insulin Hypothalamus Cholecystokinin Brain stem/Vagus GLP-1 Local GI/diverse

Ghrelin

Orexigenic Hypothalamus

A. ADIPOCYTE-DERIVED SIGNALS There is a mature and growing literature on the roles of several adipocyte products (including nonesterified fatty acids, adipocytokines, and leptin) in the regulation of metabolic fuel economy, energy balance, glucoregulation, food intake, and body weight. Products such as nonesterified fatty acids have long been proposed as mediators of obesity-associated insulin resistance and glucose dysregulation (33–35), as discussed elsewhere in this book.

B. ADIPOCYTOKINES The adipocytokine TNF-alpha (also known as cachectin, for its association with cachexia or wasting) is a mediator of insulin resistance and is secreted in higher amounts by adipocytes from obese subjects (36–41). Other circulating and adiposederived proinflammatory cytokines also have been implicated in the pathogenesis of obesity-associated insulin resistance and diabetes (42, 43). On the other hand, adiponectin is secreted in abundant amounts by fat cells from insulin-sensitive persons and is deficient in persons with obesity or insulin resistance (44, 45). Thus, numerous adipose tissue products serve as markers, signals, or modulators of energy balance, fuel economy, intermediary metabolism, glucoregulation, and other metabolic events that intersect with food intake and body-weight homeostatsis. Of these numerous adipose tissue products, leptin is perhaps the best characterized in terms of its role in the regulation of food intake and related mechanisms.

C. LEPTIN The positional cloning of the mouse (ob) gene and its human homologue (46) represents a major milestone in obesity research. Two separate mutations of the ob gene result in either a premature stop codon or complete absence of ob mRNA in the ob/ob mouse (46). The resultant absence of a normal ob gene product leads to

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overfeeding, massive obesity, delayed sexual maturation, and immune defects in ob/ob mice. The human ob or lep gene is transcribed and translated into a secreted protein mainly in white adipose tissue, but activity can also be reported in brown adipose tissue and gastric epithelium (47). Circulating leptin levels are increased by feeding, decreased during fasting or following weight loss, and are altered by a variety of hormonal and physiological factors (48, 49). A pedigree with severe childhood obesity associated with deletion of a guanine nucleotide in codon 133 of the human lep gene was the first human example of congenital leptin deficiency to be identified (50). A missense lep mutation in codon 105 has also been identified in a Turkish pedigree (51). Three individuals (two female, one male) homozygous for this mutation have the phenotype of hypoleptinemia, marked hyperphagia, massive obesity, and hypothalamic hypogonadism. Excluding these rare reports, common forms of human obesity do not appear to be caused by discernible lep mutations (52). Treatment with recombinant leptin results in a marked reduction in food intake and profound weight loss in ob/ob mice (53, 54). Leptin therapy also is remarkably effective in correcting obesity in humans with congenital leptin deficiency (55–57). 1. Mechanism of Leptin Action Leptin exerts its effects through interaction with cognate cell membrane receptors (lep-r) (58). One full-length (isoform-b) and several alternatively spliced forms (a, c, d, e, f) of lep-r have been identified in brain and peripheral tissues (59, 60). Lepr is a member of the class 1 cytokine receptor family (61). This receptor family mediates gene transcription via activation of the jak-stat pathway (42). The long isoform lep-r (b), expressed in the hypothalamus, mediates the central effects of leptin; the shorter isoforms are truncated in the cytoplasmic domain, but can bind leptin and probably mediate in some of its peripheral action (62). Leptin-receptor activation results in decreased expression of NPY, thereby inhibiting the powerful orexigenic effects of NPY (63). Leptin’s action to suppress food intake is mediated through an elaborate neuronal circuitory that involves suppression of orexigenic signals (NPY, AgRP, MCH, hypocretins 1 and 2/orexins a and b) and activation of anorexigenic (alpha-MSH, MC4, CRH, CART) neuronal pathways (23). Mutations in the lep-r gene result in obesity and leptin resistance in rodents (64, 65) and humans (66). Adipose tissue lep mRNA (67, 68) and circulating leptin (69) levels are elevated in obese subjects, suggesting that obese persons are not responding optimally to the weight-regulating effects of leptin. The basis of this leptin resistance is unclear, but may be related to impaired blood-to-brain leptin delivery (70) or defects in leptin-receptor signaling, probably mediated by altered expression of the suppressor of the cytokine signaling (socs)-3 gene in leptin-responsive cells (71). 2. Leptin and Insulin Action Replacement doses of recombinant leptin, administered systemically, normalized plasma glucose and insulin levels in hyperglycemic, hyperinsulinemic ob/ob mice

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(54) and leptin-deficient subjects with diabetes and insulin resistance (57). Low doses of leptin administered either i.v. or i.c.v. increased glucose utilization and decreased hepatic glycogen storage in wild-type mice (72). Furthermore, leptin therapy selectively depletes visceral fat stores and stimulates insulin sensitivity in rats (73). These findings indicate that leptin is a naturally occurring insulin sensitizer. Indeed, addition of leptin to cultured human hepatocytes stimulates signaling along the phosphatidyl inositol 3’ kinase pathway, one of the mediators of insulin action (74). Reversal of lipotoxicity may be another mechanism for the insulin-sensitizing effects of leptin (75). There is a marked variability in plasma leptin levels (even among persons of comparable adiposity), at least part of which may relate to differences in insulin sensitivity (48, 76). Basal (fasting) plasma leptin levels are similar in patients with diabetes compared with body mass index (BMI)- and gender-matched nondiabetic subjects (77, 78), but dynamic leptin response to secretagogues is attenuated in patients with diabetes (78, 79) or morbid obesity (80). We have postulated that increased leptin secretory response to food (as well as insulin and glucocorticoids) represents a counterregulatory attempt (48, 49, 81) to limit hyperphagia and weight gain (Figure 1.1). This adaptation may be of physiological relevance, because fasting abolishes the plasma leptin response to glucocorticoids (82, 83). Theoretically, a defect in leptin secretion could permit hyperphagia, promote weight gain, and aggravate insulin resistance. If impaired leptin secretion is confirmed as a general feature of diabetes, such diabetic dysleptinemia would provide a rationale for evaluation of leptin therapy. Indeed, patients with lipodystrophic diabetes and leptin deficiency respond remarkably well (+) NPY(–)

Hypothalamus

(+) (–) FEEDING (Insulin (–) resistance) Gcs (–) (lipolysis)

(+) (–) MEDIATORS

(+) (–) LEPTIN

(Glucose, insulin, PP, etc.)

Adipocyte

FIGURE 1.1 Glucocorticoid-leptin interactions. Glucocorticoids stimulate hypothalamic neuropeptide Y (NPY) expression, which stimulates food intake. Leptin inhibits NPY expression and induces satiety. Local gastrointestinal signals from putative postprandial mediators, such as glucose, insulin, pancreatic polypeptide (PP), Peptide YY (PYY), or other gastrointestinal humors (broken lines) may play a role in satiety, besides the suppressive action of leptin on NPY. Glucocorticoids also stimulate leptin synthesis and secretion, which could counteract the orexigenic effect of NPY. (+, stimulation; –, inhibition). (From Dagogo-Jack, S, Diabet. Rev., 7:23–38, 1999, with permission.)

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to leptin replacement, and often achieve independence from insulin and oral hypoglycemic agents (84). Leptin also potently reduced hepatic steatosis in these patients (84). 3. Exogenous Leptin Therapy for Human Obesity Administration of low physiological doses of recombinant methionyl-human-leptin (0.01-0.04 mg/kg) produced dramatic results in morbidly obese leptin-deficient patients (55–57). Following daily subcutaneous injection of recombinant leptin, significant weight loss was reported within two weeks. The weight loss was maintained at a rate of approximately 1–2 kg per month, without evidence of tachyphylaxis, throughout the period of treatment. Daily food consumption (and food-seeking behavior) decreased within one week of initiation of leptin replacement, and 95 percent of the total weight loss was accounted for by selective body-fat depletion. Basal energy expenditure decreased (due to weight loss), but dynamic energy expenditure increased during leptin treatment, the latter being due to increased physical activity (55). Thus, the major mechanisms of weight-loss following leptin replacement are sustained reduction in caloric intake and stimulation of physical activity. The stimulatory effect of recombinant leptin on physical activity was first noted in ob/ob mice (53, 54) and is probably mediated by activation of the sympathetic nervous system (85). Similar but less dramatic benefits on weight reduction were observed following leptin augmentation in a cohort of 54 lean and 73 obese men and women with normal leptin genotype (as indicated by baseline serum leptin levels > 10 ng/ml) (86). The subjects were randomized to daily self-injection with placebo or different doses (0.01, 0.03, 0.10, or 0.30 mg/kg) of recombinant methionyl human leptin. The mean weight changes at 24 weeks ranged from –0.7 ±5.4 kg for the 0.01 mg/kg dose to –7.1 ± 8.5 kg for the 0.3 mg/kg dose. As in patients with congenital leptin deficiency, loss of fat mass accounted for most of the weight loss following leptin treatment. However, there was a marked heterogeneity in the responses to recombinant leptin among subjects with normal leptin gene. Thus, leptin-deficient patients are exquisitely more sensitive to leptin therapy than patients with common obesity. Nonetheless, augmentation of circulating leptin levels induces variable but significant weight loss in leptin-replete obese subjects. This suggests that leptin resistance may be overcome by exogenous supplementation, similar to the experience with insulin therapy in type 2 diabetes. The currently known metabolic and behavioral effects of leptin are summarized in Table 1.3.

VII. PANCREATIC SIGNALS A. INSULIN Insulin was the first peripheral signal shown to regulate food intake through interaction with central-hypothalamic neurons (87). Protagonists of popular diets have claimed in the lay press that limitation of insulin secretion is the mechanism for hunger control in subjects fed low-carbohydrate, ketotic diets. Yet, the scientific

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TABLE 1.3 Behavioral and Metabolic Effects of Leptin Behavioral Inhibition of food intake (55–57) Stimulation of physical activity (53–55) Body composition Induction of fat-mass loss (55–57) Preservation of lean-muscle mass (55–57) Preservation of bone mass (55–57) Glucoregulation Improvement in insulin sensitivity (54, 57, 72, 84) Improvement in glucose tolerance (54, 57, 84) Visceral Reversal of hepatic steatosis (73, 84)

evidence strongly disputes that claim. Insulin fulfills the role (shared by leptin) of serving as a marker of adipose tissue mass and is secreted in direct proportion to fat mass. Insulin secretion also serves as an acute response to caloric influx: Increased secretion begins within minutes of initiation of feeding, is maintained for the duration of food intake, and returns to basal secretory rate in the postabsorptive period. If insulin were an appetite stimulant (like ghrelin), its secretion would have preceded, not followed, ingestion of food. The timing and pattern of postprandial insulin secretion suggest a role in the regulation of satiety and meal termination. Indeed, direct administration of insulin to the central nervous system suppresses food intake in rodents (88). Since circulating insulin reaches the central nervous system via receptor-mediated transport across the blood-brain barrier, it is possible that peak insulin levels attained during feeding trigger central mechanisms that mediate satiety. Postprandial insulin secretion also is a potent signal for leptin secretion (48). Thus, in addition to a direct effect, insulin could exert anorectic effects via a leptin-mediated mechanism. Paradoxically, diabetic patients treated with exogenous insulin or medications that increase insulin secretion or sensitivity tend to gain weight. Although several mechanisms explain the weight gain during intensive diabetes therapy, additional putative mechanisms include “central” insulin resistance and diabetic dysleptinemia (78–80).

B. PANCREATIC POLYPEPTIDE Pancreatic polypeptide (PP) is secreted by specialized endocrine cells located within the pancreatic islets of Langerhans. Plasma levels of PP increase after meals in proportion to meal size, as well as during insulin-induced hypoglycemia. The increased plasma PP level during insulin-induced hypoglycemia is a marker of cholinergic or parasympathetic activation and may have little bearing on the

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metabolic role of PP under normal physiological conditions. Postprandial PP levels probably add to the physiological satiety-signaling cascade that limits hyperphagia and helps maintain interprandial intervals. In this regard, systemic administration of PP has been shown to reduce food intake in rodents (89). Furthermore, administration of PP in patients with chronic pancreatitis has been shown to improve glucose tolerance (90). Thus, circulating PP levels, though not a major determinant of caloric balance, may be part of the afferent signals that transmit metabolic information to higher centers. However, little mechanistic information is available for the possible anorexigenic action of PP. The related peptides PP, PYY, and NPY bind to G-proteincoupled transmembrane receptors Y1–Y5 that have different affinities for each of the ligands: PP binds to Y4 and Y5 receptor subtypes expressed in the hypothalamus and other tissues (7, 8, 91). Thus, it is possible that circulating PP levels exert their effects through interaction with central receptors in a manner that antagonizes the orexigenic effects of NPY.

VIII. GASTROINTESTINAL PEPTIDES A. GHRELIN The polypeptide ghrelin was initially described and characterized as the endogenous ligand for the growth hormone secretagogue receptor in 1999 (92). The ghrelin molecule contains 28 amino acids and an acyl radical, the latter being essential for biological effect. Ghrelin is synthesized and secreted principally by the oxyntic cells of the stomach, reaches the anterior pituitary via the circulation, and stimulates growth-hormone secretion by the somatotrophs. The nutritional effects of ghrelin became evident when it was shown that central (i.c.v.) administration potently increased food intake in rodents (93). A similar effect on food intake was observed following peripheral (i.v.) injection of ghrelin in rats (93). In humans, intravenous administration of ghrelin stimulates food intake by ~30 percent (94). Interestingly, ghrelin is the only metabotrophic peptide thus far identified that stimulates food intake directly when administered peripherally. Physiological studies have indicated that ghrelin serves as a peripheral signal for hunger and meal initiation: Blood levels increase during fasting, peak sharply just before feeding, and fall rapidly following food intake (95). Prolonged administration of ghrelin in rodents leads to chronic hyperphagia and weight gain, and obese persons typically have high plasma leptin and low ghrelin levels (96). There is a diurnal rhythm in ghrelin secretion, with peak levels in the morning and the nadir at night (95). The mechanism of action of ghrelin involves stimulation of hypothalamic neurons (97) and inhibition of gastric vagal afferent signals (98). Based on the foregoing, it is plausible that ghrelin or its analogues could be candidates for future therapy for primary anorexia as well as the anorexia and cachexia often seen in patients with HIV/AIDS, systemic disorders, and malignant diseases. Conversely, ghrelin antagonism is an attractive idea for drug development for obesity and hyperphagic disorders.

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B. PEPTIDE YY The gut-derived peptideYY (PYY) is a member of a family of structurally related peptides that includes PP and NPY (7, 8, 91). PYY is synthesized by the mucosal endocrine L cells, which are located in the small intestine and large bowel. PYY336 is the major isoform secreted into the circulation (98). Feeding is a major stimulus for the release of PYY, which then serves as an anorectic/satiety signal from the intestinal cells. The potent, anorectic effect of PYY3-36 has been demonstrated in rodent studies involving direct administration of PYY3-36 into the arcuate nucleus. In human volunteers, peripheral administration of PYY3-36 inhibited food intake by 30 percent compared with placebo (99). PYY3-36 appears to exert its anorectic effect through coordinate inhibition of orexigenic NPY neurons and stimulation of POMC neurons in the arcuate nucleus. These molecular changes are observed following peripheral administration of PYY336 (99). High-affinity hypothalamic Y receptors are the target of PYY3-36 action. Activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Consonant with this mechanism, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (99). Notably, the NPY neurons in the arcuate nucleus are the central integrating sites for numerous peripheral signals (including leptin, insulin, PYY3-36, and ghrelin) that regulate food intake. Initial experience indicates that PYY3-36 is well tolerated and effective in suppressing appetite over the short term in human studies (100). Clearly, PYY or its analogues hold immense promise as candidates for obesity-drug development.

C. GLUCAGON-LIKE PEPTIDE-1 Glucagon-like peptide-1 (GLP-1) is derived from the precursor molecule preproglucagon. Site-specific cleavage of prepro-glucagon in the pancreas results in glucagon, whereas in the intestinal endocrine L cells the result is GLP-1. Both GLP-1 and PYY are cosecreted by the intestinal L cells in response to the arrival of nutrients in the gut. Like PYY, GLP-1 also appears to serve as a gut-derived satiety signal. Administration of GLP-1 into the cerebral ventricles results in marked inhibition of feeding in rodents (101). GLP-1 often is described as an incretin because of its effect in boosting postprandial insulin secretion. Additional glucoregulatory actions of GLP-1 include suppression of glucagon secretion and prolongation of gastric emptying (102). GLP-1 can induce modest weight loss probably through inhibition of food intake, induction of satiety, and delay in gastric emptying (103). In clinical trials, subcutaneous injection of GLP-1 before each meal in patients with diabetes resulted in improvement in glycemic control without untoward effects (104). Exendin-4, a GLP-1 receptor agonist with longer biological action than GLP1, also is showing promise in clinical trials (105). Endogenous GLP-1 abundance can be augmented by inhibition of dipeptidyl peptidase-4 (DPP4), the enzyme involved in GLP-1 breakdown. Such a strategy using a novel DPP-4 inhibitor (NVP DPP728) has been reported to improve glycemic control in subjects with diabetes (106). Thus, GLP-1 appears to be an intestinal satiety factor with diverse metabolic effects favorable for control of hyperglycemia. Not surprisingly, there are current

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efforts that are focused on developing novel antidiabetic agents based on GLP-1 augmentation, as reviewed elsewhere in the book.

D. CHOLECYSTOKININ Cholecystokinin (CCK) is best known for its role in food digestion, namely stimulation of pancreatic-enzyme secretion and gallbladder contraction. However, CCK has been recognized as a potent satiety factor for more than three decades (107). Peripheral and central mechanisms appear to mediate the anorectic/satiety effects of CCK. Peripherally, activation of CCKA receptors on vagal nerve endings and pyloric sphincter reduces food intake (108). Centrally, interactions between CCK and leptin pathways elicit synergistic anorectic effects; an additional mechanism of action of CCK might also involve activation of brain stem neurons that regulate portion size (8, 109). The effect of peripheral administration of CCK usually is transient and more consistent with a modulatory effect on satiety/meal termination rather than primary inhibition of meal initiation (108, 110). To induce durable inhibition of food intake, high doses and prolonged administration of CCK have been tried, but success has been limited by rapid development of tolerance (111).

IX. CONCLUSIONS An elaborate network of central and peripheral neurohormonal signals has evolved to regulate feeding, one of the primal activities necessary for survival and selfpreservation. Despite decades of animal and human research, the full extent of the processes and humors involved in the regulation of food intake remains to be elucidated. Current understanding indicates that energy homeostasis in health is predicated upon a balance between orexigenic and anorexigenic factors, both centrally and peripherally. Virtually all of the peripheral signals (e.g., insulin, PYY, leptin, CCK) are triggered by food ingestion and attenuated by fasting or starvation, indicating a response system that is tailored at satiety and meal termination. Ghrelin, the only peripheral signal activated preprandially, may be unique in its role as a rare peripheral signal for hunger and meal initiation. The rarity of peripheral hormonal signals that trigger meal initiation may be a reflection of the incompleteness of current understanding. However, a more plausible explanation is that appetite and hunger are under predominantly central control, and are orchestrated by neuronal projections from various brain centers to the NPYexpression arcuate neurons. The central control of feeding is organized into an integrated neuroendocrine system that either stimulates or inhibits food intake. The orexigenic (e.g., NPY, AgRP) and anorexigenic (e.g., melanocortins) components of this system receive afferent neuroendocrine and metabolic signals from the periphery but may also be subject to local and paracrine influences, as well as inputs from higher brain centers. The coordinate regulation of these various opposing mechanisms leads to energy homeostasis that is physiologically skewed toward positive balance. An increased understanding of these mechanisms is a prerequisite for the discovery of drug interventions that can dependably modulate food intake and prevent or treat obesity.

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ACKNOWLEDGMENTS Dr. Dagogo-Jack is supported in part by NIH Clinical Research Center Grant MO1 RR00211.

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The Enteroinsular Axis Linda M. Morgan, Ph.D.

CONTENTS I. Introduction..................................................................................................27 II. The Enteroinsular Axis and Insulin Secretion ............................................28 A. GIP.......................................................................................................28 B. GLP 1 ..................................................................................................30 III. Extrapancreatic Effects of GIP and GLP 1.................................................31 A. GIP — The Obesity Hormone? ..........................................................31 B. GLP 1 — A Spectrum of Antidiabetic Actions..................................33 IV. The Enteroinsular Axis in Diabetes ............................................................33 V. Therapeutic Aspects of GIP and GLP 1 .....................................................34 A. Type 2 Diabetes Mellitus ....................................................................34 B. Obesity.................................................................................................37 VI. Conclusions..................................................................................................37 References................................................................................................................38

I. INTRODUCTION The concept that signals arising from the gut have the ability to affect endocrine responses and the disposal of carbohydrates has a long history that has classically centered around the modulation of insulin secretion. At the turn of the century, Moore tried to treat diabetics with injections of gut extracts, suggesting that “the duodenum does yield a chemical excitant for the internal secretion of the pancreas.” In the 1930s, Heller proposed a duodenal extract that reduced postprandial hyperglycemia, which he named duodenin, but interest in it waned because the active constituent could not be isolated. However, in the 1960s, a series of classical studies [1, 2] demonstrated that the insulin response to oral glucose was up to 50 percent greater than that observed after an IV glucose infusion providing similar glucose levels, and the search was on to isolate the gut factors responsible for this effect. The term enteroinsular axis [3] was coined to embrace all those factors that contributed to enhance insulin secretion after a meal, and the putative gut hormones were called incretins. Many of the gastrointestinal hormones show a large degree of structural homology and can be divided up into distinct families on the basis of similarities in their amino-acid sequences and biological activities. The secretin family forms one such group, and many of its members have the ability to stimulate

27

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insulin when administered in pharmacological amounts. However, only two hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP 1), have the ability to act as physiological incretins. GIP was isolated from porcine intestine in 1969, and, initially characterized for its ability to inhibit gastric-acid secretion, was named gastric-inhibitory polypeptide. However, it was quickly found to be a potent insulin secretogogue [4, 5] and was renamed glucose-dependent insulinotropic polypeptide (retaining the acronym GIP) to reflect the biological role which was perceived to be the more relevant. GIP alone does not account for the entire incretin effect, as was demonstrated initially by the retention of an incretin effect following GIP immunoneutralization [6] and, subsequently, in studies with GIP receptor antagonists [7]. A second biologically active incretin, GLP 1, was later identified. GLP 1, the product of differential processing of the preproglucagon gene in the gut, is a powerful insulinotropic factor, more powerful, on a molar basis, than GIP [8]. The relative importance of these two hormones in the enteroinsular axis, particularly in diabetes, is a source of continuing debate, [9, 10] but together they account for most, if not the entire, incretin effect.

II. THE ENTEROINSULAR AXIS AND INSULIN SECRETION A. GIP GIP is a 42 amino-acid peptide secreted from specific endocrine cells, the K cells, which have the highest density in the upper part of the small intestine. In man, GIPrelease studies in response to glucose stimulation have confirmed the proximal small intestine to be the major, but not exclusive, site of endogenous GIP release, as small quantities of GIP are also released from the distal small intestine, by cells in which GIP and GLP 1 are colocalized [11]. In addition to carbohydrate, GIP secretion is also stimulated by fat and amino acids [12], though in practice, protein ingestion, per se, is not an important nutritional stimulus for GIP release, as protein is largely absorbed as dipeptides or tripeptides, which do not stimulate release of the hormone (Figure 2.1). Its secretion is dependent upon the absorption of nutrients rather than their mere presence in the gut lumen, and monosaccharide perfusion studies in rats have shown that it is only those sugars actively transported via the SGLT1 transporter that stimulate GIP secretion [13]. Studies in pigs fitted with mesenteric and hepatic portal cannulae have shown that the rate of GIP secretion is proportional to the rate of glucose absorption from the gut [14]. The magnitude of the GIP response increases with the glucose load ingested, thus the contribution of the enteroinsular axis to insulin secretion is proportionately greater when large carbohydrate loads are ingested, or when mixed meals of fat and carbohydrate are consumed. GIP is insulinotropic both in vitro, in isolated islets, or perfused pancreas, and in vivo in both animals and humans, provided that the prevailing circulating glucose concentration is above a threshold of approximately 6 mmol/l [15]. This glucose dependence of GIP provides a safeguard against inappropriate insulin secretion and hypoglycemia as a consequence of fat-stimulated GIP secretion. In addition to insulin secretion, GIP also enhances insulin-gene expression [16], the growth, differentiation, and

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Plasma GIP (pmol/l)

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FIGURE 2.1 Plasma GIP and GLP 1 in healthy human subjects following 375 Kcal meals of glucose (), protein () or fat (●). (Mean + SEM, n = 8). From Elliott, RM, et al., Glucagonlike peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol, 138, 159, 1993. Reproduced by permission.

proliferation of pancreatic B cells [17, 18], and acts as a Β cell mitogenic and antiapoptopic factor [19], thus acting as a true insulinotropic agent. An intact N-terminal is necessary to preserve GIP’s insulintropic activity, but studies with synthetic GIP/GLP 1 chimeric peptides have indicated that the entire GIP sequence is important for receptor recognition [20]. The truncated peptide GIP(3-42)amide has been shown to act as a receptor antagonist and contains a highaffinity receptor-binding region [21]. These factors are important, as both GIP and GLP 1 are rapidly and extensively degraded in vivo by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV) to produce their respective N-terminally truncated metabolites [22], thus diminishing the biological activity of the two hormones (see also the following section). The receptor for GIP is distinct from that for GLP 1, but both belong to the superfamily of G-protein-coupled receptors and are functionally coupled to the adenylate cyclase system. Interaction of GIP with its receptor on the pancreatic B cells increases intracellular calcium concentrations and enhances exocytosis of insulin-containing granules. Activation of mitogen activated protein (MAP) kinase and P13 kinase/protein kinase B signaling pathways have been implicated, secondary to the rise in cyclic adenosine monophosphate (AMP) in this process [23, 24].

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B. GLP 1 GLP 1 shares many similarities with GIP in terms of its insulinotropic activity, and numerous studies have demonstrated its insulinotropic activity in vitro and in vivo [25]. It is a 30-amino-acid peptide secreted from the L-cells of the intestinal mucosa, which occur predominantly in the lower part of the small intestine and in the colon. In common with GIP, GLP 1 secretion is stimulated by carbohydrate and fat [26], but it is also stimulated by protein (2. 1). However, circulating levels of GLP 1(736)amide, the GLP 1 isoform that is bioactive, are severalfold lower than those of bioactive GIP. In contrast to GIP, GLP 1 secretion is not dependent upon nutrient absorption, and secretion can be elicited by the presence of nutrients in the gut lumen. Regulation of GLP 1 secretion by nutrients is complex and involves both direct and indirect mediators. While glucose and long-chain fatty acids in the lumen of the gut can exert direct stimulatory effects on the GLP 1 secretion, the physiological significance of this is questionable. GLP 1 secretion occurs very rapidly after nutrient ingestion, whereas the L-cells are located mainly in the distal part of the intestine, where, under normal conditions of feeding, lumenal glucose concentrations are far below the apparent limit of sensitivity of the L-cell. It therefore seems likely that the early GLP 1 response to ingested nutrients is mediated via a proximal-distal loop involving hormonal or neural signals generated from the upper small intestine [27]. Like GIP, GLP 1’s insulinotropic activity is strictly glucose-dependent, and it has no effect on glucose concentrations below ~ 4.5 mmol/l [28]. GLP 1 also has trophic effects on pancreatic B cells. It stimulates all stages of insulin biosynthesis, as well as insulin-gene transcription [29], stimulates B cell proliferation, and enhances the differentiation of new B cells [30]. GLP 1 has also been shown to mediate endocrine proliferation in aging glucose-intolerant rats, with a resulting improvement in glucose tolerance [31], raising the exciting possibility that it might be capable of stimulating the growth of new cells in type 2 diabetic patients. An intact N-terminal is also necessary to preserve GLP 1’s insulinotropic activity, and the N-terminally truncated peptide, the product of DPP-IV cleavage, acts as a receptor antagonist [32]. GLP 1 is particularly sensitive to degradation by DPP-IV. Whereas approximately half an infusion of exogenous GIP remains intact in vivo, as little as 10 percent to 20 percent exogenous GLP 1 survives in intact form following infusion of the peptide. This rapid degradation of GLP 1 (and to a lesser extent, GIP) represents a major difficulty associated with attempting to utilize these hormones as potential therapeutic agents in diabetes. The relative importance of GIP and GLP 1 in stimulating insulin secretion in healthy human subjects is difficult to resolve. Circulating levels of GIP following nutrient ingestion are some fourfold to fivefold higher than GLP 1, although in molar terms, GLP 1 has been shown to be a more potent insulin secretagogue than GIP [8]. Most current radioimmunoassays for GIP and GLP 1 measure precursors and inactive metabolites in addition to the biologically active hormone, making interpretation of physiological postprandial levels of the hormones difficult. A study using GIP-receptor antagonists in genetically obese mice concluded that GIP might be responsible for as much as 80 percent of the incretin effect in these animals [21]. However, similar studies in humans involving GLP 1 receptor antagonists [33] have

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shown that GLP 1 is responsible for a substantial part of the insulin response to oral glucose. Recent studies in humans, involving infusion of physiological concentrations of the biologically active hormones while circulating glucose levels were clamped at fasting, or slightly raised in order to mimic the postprandial state, have concluded that the two hormones contribute almost equally to the incretin effect of a meal, and do so in an additive manner [34]. This finding has been corroborated in recent experiments in mice with a double knock-out of both GIP and GLP 1 receptors [35], where preliminary results are consistent with the additive effects of the two hormones. However, GLP 1 is additionally very effective in minimizing changes in postprandial glycemia because of its capacity to delay gastric emptying and inhibit glucagon secretion (see next section). Thus, in the physiological setting of meal ingestion where whole-body glucose metabolism is considered, the insulinotropic effect of GLP 1 can be obscured by these effects, demonstrating that the regulation of circulating glucose levels via the enteroinsular axis does not operate solely via the effects of the incretin hormones on insulin secretion.

III. EXTRAPANCREATIC EFFECTS OF GIP AND GLP 1 A. GIP — THE OBESITY HORMONE? GIP receptor mRNA has been found in a variety of tissues outside the pancreas, including stomach, intestine, brain, heart, and adipose tissue. The function of GIP in many of these tissues remains unclear, but a role of GIP in adipose-tissue metabolism and a possible function in the development of obesity has recently generated much interest. Fat is a potent secretagogue of GIP in humans, and functional GIP receptors have been identified on adipocytes [36]. Twenty-four-hour secretory patterns of GIP in humans closely parallel those of plasma triglyceride, suggesting a possible role in postprandial lipid clearance and metabolism [26], a hypothesis strengthened by the finding that infusion of GIP promotes the clearance of chylomicron triacylglycerol (TAG) in dogs [37]. Consistent with this hypothesis, hypertriglyceridemic subjects have been shown to exhibit disordered postprandial GIP secretion [38]. In various adipose-tissue preparations in vitro, GIP augments insulin-stimulated glucose transport [39], increases fatty-acid synthesis [40], and reduces glucagonsstimulated lipolysis [41], demonstrating a direct insulin-like anabolic role. In man, accumulation of TAG in adipose tissue from dietary fat sources is quantitatively much more important than de novo lipogenesis. Adipose tissue lipoprotein lipase (LPL) plays a key regulatory role in postprandial TAG clearance by hydrolyzing chylomicron and very low density lipoprotein (VLDL) TAG and liberating fatty acids for uptake and storage within the adipocyte. GIP, in common with insulin, increases LPL activity in rat adipose-tissue explants, whereas GLP 1 is without effect [42]. The magnitude of the postprandial GIP response in humans is dependent on the size of the fat, as well as the carbohydrate load [43], and progressive increases in postprandial postheparin LPL activity in parallel with plasma GIP have been found when the fat content of the meal is increased [43]. These findings are consistent with GIP acting as a major hormonal signal linking meal size with LPL

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activity in the physiological control of postprandial lipemia, in addition to its effects on postprandial glycemia. These actions of GIP have led to the hypothesis that the hormone might play a role in the etiology of obesity. GIP secretion is sensitive to chronic changes in diet, in particular, to changes in the dietary fat content; diets high in fat content increase intestinal K cell number [44], GIP expression, and circulating GIP levels [45]. Obesity is typically associated with hyperinsulinemia, and the anabolic activity of GIP could combine with insulin to promote adipose tissue fat deposition. The gene encoding GIP could be considered a thrifty gene, maximizing nutrient storage and valuable to our hunter/gatherer forebears. However, this feature of GIP physiology could be maladaptive in people consuming energy-dense, fat-rich Western diets, and could contribute towards their obesity (Figure 2.2). The hypothesis has gained much recent support from studies of GIP-receptor knock-out mice (GIPR–/–) in which GIPreceptor expression is disrupted. In contrast to normal control animals, these mice did not gain weight or become obese when placed on a high-fat diet. Food intake was not significantly different between the two groups, but the GIPR–/– mice exhibited a higher energy expenditure and appeared to oxidize triglycerides preferentially. In addition, crossing hyperphagic, genetically obese ob/ob mice with GIPR–/– mice reduced the severity of obesity by 23 percent in their homozygous offspring. These Hyperphagia (high fat diet)

Elevated GIP (K-cell hyperplasia)

GIP receptors Actions on adipose tissue

Increased fat stores Obesity

GIP receptors Hyperinsulinaemia (beta-cell hyperplasia)

Insulin resistance

Glucose intolerance

Hyperglycaemia Diabetes

FIGURE 2.2 Scheme linking overnutrition to the development of obesity, insulin resistance, and type 2 diabetes, via GIP. From Gault, VA, O’Harte, FPM, and Flatt, PR, Glucosedependent insulinotropic polypeptide (GIP): antidiabetic and antiobesity potential? Neuropeptides, 37, 253, 2003. With permission from Elsevier.

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findings collectively indicate that GIP is an important hormone in lipid metabolism, which links overnutrition with the development of obesity.

B. GLP 1 — A SPECTRUM

OF

ANTIDIABETIC ACTIONS

GLP 1 is established as a physiological incretin, promoting insulin secretion and exerting trophic effects on the pancreas. However, it has other extrapancreatic biological actions, which could be highly desirable in the context of treating type 2 diabetes. GLP 1 delays gastric emptying [46], slowing down glucose absorption and thus reducing postprandial glucose excursions. It is also a potent inhibitor of glucagon secretion, and is able to lower glucose levels in insulin-requiring diabetic patients with no residual Β cell activity (hence, no capacity for insulin secretion) by attenuating the hyperglycemic action of glucagons [47]. GLP 1 has also been shown to enhance glucose uptake and glycogen storage in liver and muscle [48]. All of these actions would contribute towards GLP 1’s hypoglycemic effect in addition to its insulinotropic action. Moreover, GLP 1 is, in addition, a short-term inhibitor of appetite and food intake, and may contribute to glucose homeostasis by reducing food intake itself [49]. This satiety effect of GLP 1 would be desirable to support attempts at weight reduction in type 2 diabetic subjects, many of whom are also obese. The finding that glucose-stimulated GLP 1 secretion is reduced in obese subjects [50] is of obvious importance in its putative role as a satiety factor. The above spectrum of antidiabetic actions place GLP 1 in a potentially good position as a therapeutic agent in the treatment of diabetes.

IV. THE ENTEROINSULAR AXIS IN DIABETES The importance of the enteroinsular axis in healthy individuals gave rise to the possibility that an incretin defect might be partially responsible for the metabolic abnormalities observed in type 2 diabetes. Several studies showed that the incretin effect (as studied by comparing isoglycemic oral and IV glucose loads) is reduced or abolished in these individuals [51]. Work in this area initially centered on the possibility of impaired GIP secretion, but early publications reached no consensus, as normal, increased, and decreased GIP secretion have all been reported in type 2 diabetes [52]. Some of these conflicting results could be attributed to the varying degrees of cross-reactivity that GIP assays displayed with biologically inactive forms of the hormone. A recent study has found normal or marginally impaired GIP secretion in diabetics drawn from a population with a wide spectrum of the disease [53]. However, similar studies with GLP 1 have shown a significant impairment of GLP 1 secretion in diabetes, which was related to impaired B cell function, regardless of whether the biologically-active intact hormone, or the metabolites of GLP 1, were measured [53]. Studies of identical twins, discordant for type 2 diabetes, have shown that GLP 1 responses are lower in the diabetic twin, and they are also normal in the first degree relatives of diabetic subjects [54]. This implies that the impaired GLP 1 secretion observed in diabetes is a consequence rather than a cause of the disease.

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However, when the biological effects of IV infusions of GIP or GLP 1 in type 2 diabetic subjects was studied, the findings did not reflect the secretory defects of the two hormones in these individuals. While the insulinotropic effect of GLP 1 was similar to that of control subjects, the insulinotropic effect of GIP was almost lost in type 2 diabetes [55]. These findings point to a GIP receptor or postreceptor defect at pancreatic Β cell level in type 2 diabetes. Defective expression of the GIP receptor has been observed in animals with genetically determined diabetes [56]. Polymorphisms in the coding region of the GIP-receptor gene have also been reported, but these have not been associated with either defective signaling or diabetes [57]. However, studies in healthy, first-degree relatives of diabetic patients showed a reduced insulinotropic effectiveness of GIP in comparison to healthy subjects without a family history of diabetes, suggesting that the GIP defect could possibly be a genetically determined, primary defect [58]. The mechanism of diminished GIP responsiveness in diabetics remains unclear. It appears to be severe, but confined to late-phase insulin secretion only, a finding that makes defective GIP-receptor expression an unlikely explanation [59]. Recent work with diabetic patients who do not conform to the classic obese type 2 pattern [60] has suggested that the defect is primarily a consequence rather than a cause of the diabetic state, although a genetic component cannot be ruled out. The impairment of both the secretion of GLP 1 and the responsiveness of GIP in type 2 diabetes explains the findings of a severely diminished or absent incretin effect in these patients. It also has implications for the use of these hormones in the treatment of diabetes, as can be seen in the following section.

V. THERAPEUTIC ASPECTS OF GIP AND GLP 1 A. TYPE 2 DIABETES MELLITUS The potent insulinotropic actions of GIP and GLP 1 and their strict glucose dependency, thereby avoiding hypoglycemia, make these hormones potentially important agents in the treatment of type 2 diabetes. GLP 1’s other antihyperglycemic actions (inhibition of glucagon secretion, gastric emptying, food intake, etc.) additionally make it particularly suited to an antidiabetic role. However, there are two major difficulties associated with using these hormones as therapeutic agents, 1) their extremely rapid degradation in circulation (particularly GLP 1), and 2) the diminished responsiveness of diabetic individuals to the insulinotropic action of GIP. This latter difficulty has resulted in most work on the therapeutic potential of the incretins in type 2 diabetes, focusing on the possible use of GLP 1 or its analogues. Continuous IV infusion of GLP 1 can effectively normalize glucose concentrations in type 2 diabetes [61], but simple subcutaneous injections are ineffective, as > 90 percent of the peptide is rapidly degraded under these circumstances [62]. However, recent studies using minipumps to deliver subcutaneous GLP 1 continuously have demonstrated a clinically significant improvement in plasma glucose and HbA1C, together with modest weight loss, over a six-week period [63] (Figure 2.3). This mode of delivery is not, however, ideal for everyday treatment.

Plasma glucose (mmol/l)

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FIGURE 2.3 Plasma glucose profiles and weight losses in type 2 diabetics before and following a six-week course of GLP 1 infusions. From Zander, M, et al., Effect of a 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 359, 824, 2002.

The observation that GLP 1 secretion is diminished in diabetics has prompted the investigation of dietary strategies to increase endogenous GLP 1 secretion. Increasing large-bowel fermentation by means of lactulose (as a model of resistant starch carbohydrate) or with viscous fiber (psyllium) is ineffective in raising GLP 1 levels [64, 65], as is the manipulation of the mono-unsaturated acid/polyunsaturated fatty acid (MUFA/PUFA) content of the diet [66]. However, the alpha-glycosidase inhibitor acarbose, used in the treatment of both type 1 and type 2 diabetes, which delays the upper-intestinal absorption of sucrose, diminishes GIP, but markedly potentiates GLP 1 secretion [67] (Figure 2.4). The therapeutic efficacy of acarbose in diabetes could be partly due to this ability to augment GLP 1 secretion. More recent strategies to enhance the action of GLP 1 in diabetes have centered around extending its biologically active half-life in the plasma by circumventing the inactivation of GLP 1 (and GIP) by DPP-IV. This has been tackled by a two-pronged approach: 1) the use of DPP-IV inhibitors, and 2) the development of degradationresistant GLP 1 and GIP analogues. Treatment with DPP-IV inhibitors promote marked improvements in glycemic control in both animal models of diabetes and in human diabetic studies [68]. A major advantage to this approach lies in the ability to administer DPP-IV inhibitors orally; however, there is also an intrinsic disadvantage due to a lack of specificity of the DPP-IV enzyme. DPP-IV exerts physiological actions on a wide range of regulatory peptides in addition to GLP 1 and GIP. Its pharmacological inactivation may therefore have other clinical consequences beyond

GIP (pmol l–1)

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FIGURE 2.4 Plasma GIP and GLP 1 in healthy subjects following a 100 g oral sucrose load, with () or without () the addition of the alpha-glycosidase inhibitor acarbose. (From Ranganath, LR, et al., Diabetic Med., 15, 120, 1998. With permission.)

its antidiabetic action, and these will need to be carefully evaluated before the clinical efficacy of DPP-IV inhibitors can be confirmed. The other approach, namely the development of specific DPP-IV-resistant GLP 1 analogues modified at the N-terminus around the enzyme cleavage site, has proved to be more promising. A number of analogues are effective in improving glucose tolerance and insulin secretion in animal models of diabetes [69]. Studies are currently in progress to extend the half-lives of these analogues still further by the attachment of acyl side-chains to selected residues; these bind to albumin and thus delay renal clearance of the analogues. More convenient forms of delivery of the peptides are also being explored, such as nasal sprays and transdermal patches, to avoid the need for frequent injections or continuous infusion of the analogues. A final approach has been the utilization of DPP-IV-resistant receptor agonists. One such, exendin-IV, a naturally occurring agonist found in the saliva of the Gila monster lizard, is an effective antidiabetic agent in a wide range of animal studies, and is currently undergoing clinical trials in type 2 diabetes [70]. While most interest in the therapeutic potential of incretins in diabetes has centered around DPP-IV-resistant GLP 1, some studies have been carried out on DPP-IV-resistant GIP analogues. GIP analogues have some potential advantages over GLP 1 in that enhanced activity is generally easier to achieve with GIP than with GLP 1 analogues, and the lack of any significant effects of GIP on gastric emptying can be advantageous when treating diabetics with neurological complications. A number of N-terminally modified GIP analogues have been developed and characterized that have a greater potency than GIP in stimulating insulin secretion and improving glucose tolerance in diabetic animal models [9], but their therapeutic

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potential in human type 2 diabetes, which is characterized by GIP insensitivity, remains to be proven.

B. OBESITY The evidence that GIP might have a role in the etiology of obesity has supported the concept of using GIP-receptor antagonists to treat obesity. Receptor antagonists based on fragments of the full-length hormone have been developed [7, 9], together with antisera that bind either to GIP itself or to the GIP receptor. These are all very effective in blocking the insulinotropic action of GIP, but the effects of chronic administration on body weight have yet to be reported [71]. The concept of GIP antagonists as antiobesity agents is an attractive one, but the antagonistic effects of such compounds on the other actions of GIP also need to be considered. Thus, chronic treatment with a GIP-receptor antagonist might worsen glucose tolerance, and interfere with postprandial triglyceride disposal, leading to increased circulating triglyceride levels and hence increased cardiovascular-disease risk. The beneficial effects of fat loss may outweigh such deleterious effects, but a note of caution should be sounded regarding the potential loss of GIP’s other beneficial actions. It remains to be seen whether GIP antagonists with spectra of biological activities that specifically target adipose tissue can be developed, thus maximizing antiobesity activity while minimizing unwanted side effects. The effect of GLP 1 in increasing satiety, hence diminishing food intake, has hitherto received very little attention in terms of its potential use as an antiobesity agent. The vast, built-in redundancy of hypothalamic satiety mechanisms, together with the observation that GLP 1-receptor knock-out mice do not become obese, indicates that GLP 1 might not be indispensable for normal appetite regulation. However, the finding that chronic GLP 1 administration in type 2 diabetes not only improves glucose tolerance but also has modest but significant beneficial effects in terms of weight loss [63] (Figure 2.3) is clearly of great interest, as the majority of type 2 diabetic individuals are overweight. Improvement of insulin sensitivity resulting from weight loss would confer an additional therapeutic advantage in these patients.

VI. CONCLUSIONS The enteroinsular axis plays an important role in promoting insulin secretion in response to food intake, and its impairment in type 2 diabetes makes a significant contribution to the impairment of glucose tolerance and insulin secretion in these individuals. Although GIP and GLP 1 initially gained recognition as insulin secretogogues, it is their trophic actions on the pancreas, together with their extrapancreatic actions, that have recently generated most interest. The tight control of GIP and GLP 1 secretion by both the size and nutrient content of a meal provides a mechanism whereby diet is linked to the metabolic fate of nutrients. GLP 1 is able to control the rate of delivery of nutrients for absorption via modulation of gastric emptying and at a higher level may affect nutrient intake itself by acting as a satiety factor. GIP regulates the postprandial disposal and deposition of lipid with its insulin-like actions on adipose tissue, in addition to its effects on carbohydrate metabolism.

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The therapeutic potential for GLP 1 or its related analogues to act as antidiabetic agents is just beginning to be realized, with encouraging clinical results. While GIP is less likely to be effective in this respect, the hypothesis that increased GIP action links overnutrition to the development of obesity points to the possible therapeutic value of GIP-receptor antagonists in the treatment of obesity. Both therapeutic aspects are areas with exciting future possibilities.

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18. Trumper, A, et al., Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling, Mol. Endocrinol., 15, 1559, 2001. 19. Trumper, A, et al., Mechanisms of mitogenic and anti-apoptotic signaling by glucosedependent insulinotropic polypeptide in beta (INS-1) cells, J. Endocrinol., 174, 233, 2002. 20. Gallwitz, B, et al., GLP 1/GIP chimeric peptides define the structural requirements for specific ligand-receptor interaction of GLP 1, Regul. Pept., 63, 17, 1996. 21. Gault, VA, et al., Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP (3-42), is a GIP receptor antagonist in vivo, J. Endocrinol., 175, 525, 2002. 22. Kieffer, TJ, McIntosh, CH, and Pederson, RA, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagons-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 136, 3585, 1995. 23. Ehses, JA, et al., Glucose-dependent insulinotropic polypeptide activates the Raf-Mek 1/2-ERK 1/2 module via a cyclic AMP-dependent protein kinase/Rap1-mediated pathway, J. Biol. Chem., 277, 37088, 2002. 24. Ehses, JA, et al., A new pathway for glucose-dependent insulinotropic polypeptide receptor signaling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion, J. Biol. Chem., 276, 23667, 2003. 25. D’Alessio, DA and Ensinck, JW, The insulinotropic gut hormone glucagon-like peptide-1, Fehmann, HC and Göke, B, Eds., Karger, Basel, p. 132, 1997. 26. Elliott, RM, et al., Glucagon-like peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol., 138, 159, 1993. 27. Holst, JJ, Glucagon-like peptide 1 (GLP 1): an intestinal hormone signaling nutritional abundance, with an unusual therapeutic potential, Trends. Endocrinol. Metab., 10, 229, 1999. 28. Weir, GC et al., Glucagon-like peptide-1 (7-37) actions on the endocrine pancreas, Diabetes, 38, 338, 1989. 29. Fehmann, HC and Habener, JF, Insulinotropic glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells, Endocrinology, 130, 159, 1992. 30. Zhou, J, et al., Glucagon-like peptide-1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells, Diabetes, 48, 2358, 1999. 31. Perfetti, R, et al., Glucagon-like peptide-1 induces cell proliferation and pancreaticduodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats, Endocrinology, 141, 4600, 2000. 32. Knudsen, LB and Pridal, L, Glucagon-like peptide-1(9-36)amide is a major metabolite of glucagon-like peptide-1(7-36) amide after in vivo administration to dogs and it acts as an antagonist on the pancreatic receptor, Eur. J. Pharmacol., 318, 429, 1996. 33. Edwards, CM, et al., Glucagon-like peptide-1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39, Diabetes, 48, 86, 1999. 34. Vilsboll, T, et al., Both GLP 1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects, Regul. Pept., 114, 115, 2003. 35. Preitner, F, et al., Disruption of both GIP and GLP 1 signalling pathways in the mouse leads to glucose intolerance Diabetes, 51, A66, 2002. 36. Yip, RCG, et al., Functional GIP receptors are present on adipocytes, Endocrinology, 139, 4004, 1998.

40

Nutrition and Diabetes: Pathophysiology and Management 37. Wasada, T, et al., Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglyceride in dogs, J. Clin. Invest., 68, 1106, 1981. 38. Gama, R, et al., Postprandial elevation of gastric inhibitory polypetide concentrations in hypertriglyceridaemic subjects, Clin. Sci., 93, 343, 1997. 39. Starich, GH, Bar, RS, and Mazzaferri, EL, GIP increases insulin receptor affinity and cellular sensitivity in adipocytes, Am. J. Physiol., 249, E603, 1985. 40. Oben J, et al., Effect of the entero-pancreatic hormones gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue J. Endocrinol., 130, 267, 1991. 41. Dupré, J, et al., Inhibition of actions of glucagons in adipocytes by gastric inhibitory polypeptide, Metabolism, 25, 1197, 1976. 42. Knapper, JM, et al., Investigations into the actions of glucose-mediated insulinotropic polypeptide and glucagons-like peptide-1(7-36) amide on lipoprotein lipase activity in explants of rat adipose tissue, J. Nutr., 125, 183, 1995. 43. Murphy, MC, et al., Postprandial lipid and hormone responses to meals of varying fat content: modulatory role of lipoprotein lipase? Eur. J. Clin. Nutr., 49, 579, 1995. 44. Bailey, CJ, et al., Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets, Acta. Endocrinol. (Copenh.), 112, 224, 1986. 45. Morgan, LM, et al., Modification of gastric inhibitory polypeptide secretion in man by a high fat diet, Br. J. Nutr., 59, 373, 1988. 46. Wettergren, A, et al., Trucated GLP 1 (proglucagon 78-107 amide) inhibits gastric and pancreatic functions in man, Dig. Dis. Sci., 38, 665, 1993. 47. Creutzfeldt, WO, et al., Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide 1(7-36) amide in type I diabetics, Diabet. Care, 19, 580, 1996. 48. O’Harte, FPM, et al., Effects of non-glycated and glycated glucagon-like peptide1(7-36) amide on glucose metabolism in isolated mouse abdominal muscle, Peptides, 18, 1327, 1997. 49. Verdich, C, et al., A meta-analysis of the effect of glucagon-like peptide-1(7-36)amide on ad libitum energy intake in humans, J. Clin. Endocrinol. Metab., 86, 4382, 2001. 50. Ranganath LR, et al., Attenuated GLP 1 secretion in obesity: Cause or consequence? Gut 38, 916, 1996. 51. Nauck, M, et al., Reduced incretin effect in type 2 (non-insulin dependent) diabetes, Diabetologia, 28, 46, 1986. 52. Krarup, T, Immunoreactive gastric inhibitory polypeptide, Endocr. Rev., 9, 122, 1988. 53. Toft-Neilsen, MB, et al., Determinants of the impaired secretion of glucagon-like peptide-1 secretion in type 2 diabetic patients, J. Clin. Endocrinol. Metab., 86, 3717, 2001. 54. Vaag, AA, et al., Gut incretins in identical twins discordant for non-insulin dependent diabetes mellitus (NIDDM) — evidence for decreased glucagon-like peptide-1 secretion during oral glucose ingestion in NIDDM twins, Eur. J. Endocrinol., 135, 425, 1996. 55. Nauck, MA, et al., Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus, J. Clin. Invest., 91, 301, 1993. 56. Lynn, FC, et al., Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats, Diabetes, 50, 1004, 2001. 57. Holst, JJ, Gromada, J, and Nauke, MA, The pathogenesis of NIDDM involves a defective expression of the GIP receptor, Diabetologia, 40, 984, 1997.

The Enteroinsular Axis

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58. Meier, JJ, et al., Reduced insulinotropic effect of gastric inhibitory polypeptide in first degree relatives of patients with type 2 diabetes, Diabetes, 50, 2497, 2001. 59. Vilsboll, T, et al., Defective amplification of the late phase insulin response to glucose by GIP in obese type 2 diabetic patients, Diabetologia, 45, 1111, 2002. 60. Vilsboll, T, et al., The pathophysiology of diabetes involves a defective amplification of the late phase insulin response to glucose by GIP — regardless of aetiology or phenotype, J. Clin. Endocrinol. Metab., 88, 4897, 2003. 61. Rachman, J, et al., Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP 1) in subjects with NIDDM, Diabetologia, 40, 205, 1997. 62. Deacon, CF, et al., Both subcutaneously and intravenously administered glucagonlike peptide-1 are rapidly degraded from the NH2 terminus in type II diabetic patients and in healthy subjects, Diabetes, 44, 1126, 1995. 63. Zander, M, et al., Effect of a 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 359, 824, 2002. 64. Frost, G, Brynes, A, and Leeds, A, Effect of large bowel fermentation on insulin, glucose, free fatty acids and glucagon-like peptide 1 (7-36) amide in patients with coronary heart disease, Nutrition, 15, 183, 1999. 65. Frost, GS, et al., The effects of fiber enrichment of pasta and fat content on gastric emptying, GLP 1, glucose and insulin responses to a meal, Eur. J. Clin. Nutr., 57, 293, 2003. 66. Brynes, AE, et al., Diet-induced change in fatty acid composition of plasma triacylglycerols is not associated with change in GLP 1 or insulin sensitivity in people with type 2 diabetes, Am. J. Clin. Nutr., 72, 1111, 2000. 67. Ranganath, LR, et al., Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its antihyperglycaemic effect. Diabetic Med., 15, 120, 1998. 68. Ahren, B, et al., Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes, Diabet. Care, 25, 869, 2002. 69. Gault, VA, Flatt, PR, and O’Harte, FPM, Glucose-dependent insulinotropic polypeptide analogues and their therapeutic potential for the treatment of obesity-diabetes, Biochem. Biophs. Res. Comm., 308, 207, 2003. 70. Perry, T, and Greig, NH, The glucagon-like peptides: a double-edged therapeutic sword? Trends in Pharm. Sci., 24, 377, 2003. 71. Kieffer, TJ, GIP or not GIP? That is the question, Trends in Pharm. Sci., 24, 110, 2003.

3

Achieving a Healthy Body Weight: Diet and Exercise Interventions for Type 2 Diabetes Connie W. Bales, Ph.D., R.D., and Jama L.Purser, P.T., Ph.D.

CONTENTS I. Introduction to the Problem: The Critical Link Between Diabetes and Excess Body Weight ...............................................................................44 II. Health Benefits of Diet and Exercise..........................................................44 A. Prevention ............................................................................................45 B. Management of Existing Disease .......................................................45 III. Lifestyle Interventions: Indications and Goals ...........................................45 A. Weight-Reduction Diets ......................................................................46 1. Indications and Body-Weight Goals for Optimal Health.............46 2. Calorie-Reduction Diets................................................................46 3. Low-Fat Diets................................................................................48 4. Low Carbohydrate and Other Nontraditional Dietary Approaches .......................................................................48 5. Comments on Overall Diet Composition .....................................49 B. Exercise Interventions .........................................................................49 1. Aerobic Exercise ...........................................................................51 2. Resistance Training .......................................................................51 3. Combination Training ...................................................................52 IV. Concluding Comments on Maintenance of Weight Loss and Improved Fitness............................................................................................52 References................................................................................................................53

43

44

Nutrition and Diabetes: Pathophysiology and Management

I. INTRODUCTION TO THE PROBLEM: THE CRITICAL LINK BETWEEN DIABETES AND EXCESS BODY WEIGHT The problem of obesity has reached epidemic proportions in the United States (see also other chapters by Boan and McMahon), and evidence of its negative impact on health is rapidly accumulating. Excessive body mass, defined as a body-mass index (BMI) over 25 kg/m2 (overweight; OW) and ≥ 30 kg/m2 (obese; OB) is linked with an increased risk for a number of serious chronic diseases, including cardiovascular disease (CVD), hypertension, and some cancers, as well as type 2 diabetes (1–3). The relationship between OW/OB and diabetes is exceedingly strong, with the prevalence of type 2 diabetes increasing along with OW/OB in a dose-dependent manner (3). In fact, as many as 90 percent of all type 2 diabetic individuals fit the OW/OB BMI criteria (4). Thus, OW/OB and type 2 diabetes are “inextricably linked” (5), the term “diabesity” having been coined by Astrup and Finer (6) to emphasize the close connection between the two disorders. The need to deal with the obesity problem by restoring optimal body mass and composition is well recognized for all segments of the adult population, but it is particularly critical for individuals with type 2 diabetes. The risk to mortality posed by obesity is greatly enhanced by the coexistence of diabetes; moreover, diabetes treatment can interfere with the ability to achieve and maintain a healthy body mass. OW/OB may also directly impact glycemic control. Due to greater hepatic or peripheral insulin resistance, type 2 diabetic patients who are OW/OB can have a reduced response to antidiabetic therapy compared with normal-weight patients, necessitating higher doses of antihyperglycemia medications (7). In addition, the risk of CVD — a major cause of mortality and morbidity in individuals with diabetes — is heightened due to OW/OB-linked hypertension and dyslipidemia. Recognizing the need for prompt, effective interventions to disrupt the cycle of OW/OB and diabetes, the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition have jointly developed and recently released a statement on the use of lifestyle modification to prevent and manage type 2 diabetes (8). The statement emphasizes the importance of lifestyle intervention as the principal therapy for OW and OB patients. In this chapter, we focus on the lifestyle modifications (diet and exercise) recommended in the statement. The utilization of weight-loss medications and bariatric surgery to aid weight loss in type 2 diabetes is discussed separately elsewhere in the book, and comprehensive reviews on the subject are available (9–10).

II. HEALTH BENEFITS OF DIET AND EXERCISE As already acknowledged, lifestyle interventions can play a critical role in preserving the health of individuals prone to developing type 2 diabetes. Interventions that reduce OW/OB can prevent the development of the disease in persons with prediabetes, and for those with established disease, a moderate weight loss helps improve glycemic control and reduces CVD risk.

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45

A. PREVENTION In the case of both OW/OB and type 2 diabetes, prevention is by far the best approach, requiring significantly less expense and effort than therapeutic interventions. Compared to individuals with a BMI of 18.5 to 24.9, persons with a BMI > 35 are 20 times as likely to develop diabetes (2, 11). As little as a 5 percent weight loss has been shown in clinical trials to prevent obese subjects with glucose intolerance from developing type 2 diabetes (6). Unfortunately, in the face of affluent lifestyles and copious amounts of readily accessible and highly palatable foods, the motivation for preventing obesity is often absent, as evidenced by current trends toward more rather than less OW/OB in the U.S. population (12). Without the presence of discernable health impairments, many individuals lack the motivation to incorporate diet and exercise regimens into their daily routines. Labor-saving devices and time constraints that favor a sedentary lifestyle also contribute to the prevalence of positive energy balance. For ready-to-change individuals (13), however, preventive nutrition measures offer dramatically beneficial effects. Results from the Diabetes Prevention Program (14) indicated a reduced four-year incidence of type 2 diabetes in men and women with glucose intolerance in response to weight reduction (7 percent loss in year one) and increased physical activity (150 minutes brisk walking/week). Tuomilehto et al. (15) followed 522 OW/OB subjects randomly assigned to a control group or a diet/physical activity intervention and reported reductions in the incidence of diabetes directly commensurate with lifestyle changes.

B. MANAGEMENT

OF

EXISTING DISEASE

It is well recognized that OW/OB complicates the management of type 2 diabetes via increased insulin resistance and blood-glucose levels (16). For persons with type 2 diabetes who are OW/OB, targeting efforts to reach a healthy BMI (ideally ≤ 25 kg/m2) is the most important goal of lifestyle interventions (17, 18). When combined with increased activity, weight loss can dramatically enhance insulin sensitivity and glycemic control (8). Improvements occur in insulin action and blood-glucose concentrations, and required doses of diabetes medications may be reduced. Reductions in fasting glucose levels correspond directly to the amount of weight reduction (8,19). Alternatively, if excess weight is not reduced, glycemic control is likely to deteriorate over time, in as little as 12 months (7).

III. LIFESTYLE INTERVENTIONS: INDICATIONS AND GOALS In order to achieve a healthy body weight and body composition, persons with diabetes who are OW/OB need to have a medically supervised program that includes a calorie-restricted (weight reduction; WR) diet and an individualized exercise program that emphasizes long-term maintenance of total body mass and preservation of muscle tissue (20).

46

Nutrition and Diabetes: Pathophysiology and Management

A. WEIGHT-REDUCTION DIETS By restoring a healthier body weight, dietary treatment (WR) in OW/OB individuals can provide significant clinical benefits. Unfortunately, the nature of diabetes and its treatment can hinder weight loss and even promote weight gain. This is because the progressive dysfunction of pancreatic B cells and increasing insulin resistance necessitate increasingly higher insulin dosages. This, in turn, promotes weight gain, and in a negative vicious cycle, makes weight loss even more difficult to achieve than for the nondiabetic obese individual (20). 1. Indications and Body-Weight Goals for Optimal Health For all OW and OB individuals who have type 2 diabetes or strong risk factors for the disease, WR is recommended. The ideal body-weight goal is to achieve a BMI of < 25 kg/m2, but it is important to set a realistic weight-loss goal that is likely to be both achievable and sustainable. As previously noted, a weight loss as small as 5 percent to 10 percent of baseline can lead to significant, positive effects on health and yet not be overwhelming as an initial goal (4, 8, 21, 22). This benefit is realized regardless of the initial weight at the time WR is initiated. 2. Calorie-Reduction Diets In designing a WR diet, both the amount of calories and distribution of energyyielding macronutrients need to be considered. A negative energy balance needs to be reached in order for weight loss to occur. Obviously, energy intake (amount of calories consumed) must be brought moderately below energy expenditure (and thus energy requirement) over time so as to achieve a safe but consistent negative balance. To determine a precise calorie prescription, energy requirements (total energy expenditures; TEE) can be calculated using published equations such as the Harris Benedict equations (23): Males: Calculated BMR = [66.5 + (13.75 × wt [kg]) + (5.003 × ht [cm]) – (6.775 × age [yr])] × PA Females: Calculated BMR = [655.1 + (9.563 × wt [kg]) + (1.850 × ht [cm]) – (4.676 × age [yr])] × PA To determine the TEE, adjustments need to be made for activity levels, as listed below: Sedentary (little or no exercise): BMR × 1.2 Lightly Active (light exercise/sports 1–3 days/week): BMR × 1.375 Moderately Active (moderate exercise/sports 3–5 days/week): BMR × 1.55

Achieving a Healthy Body Weight

47

Very Active (hard exercise/sports 6–7 days/week): BMR × 1.725 Extra Active (very hard daily exercise/sports and physical job or twice-daily training): BMR × 1.9 The TEE can also be calculated using the predictive equations derived from studies with doubly-labeled water and recently published by the Food and Nutrition Board of the Institute of Medicine (24). The following equations were developed for use in overweight individuals aged 19 years and older: Males: TEE = 864 – 9.72 × age [yr] + PA × 14.2 x wt [kg] + 503 × ht [m] Females: TEE = 387 – 7.31 × age [yr] + PA × (10.9 × wt [kg] + 660.7 × ht [m] Where PA is the physical activity coefficient: PA = 1.00 if PAL is estimated to be ≥1.0 <1.4 (Sedentary) PA = 1.11 if PAL is estimated to be ≥1.4 <1.6 (Low Active) PA = 1.25 if PAL is estimated to be ≥1.6 <1.9 (Active) PA = 1.48 if PAL is estimated to be ≥1.9 <2.5 (Very Active) A calorie-intake decrease of 500–1000 Kcal/day will usually result in a moderate but steady weight loss (1–2 lb/wk or 0.45–0.90 kg/wk). Table 3.1 provides some estimated Kcal reductions based on body-mass ranges. Generally, WR regimens should supply a minimum of ≥ 1000–1200 Kcal/d for women and ≥ 1200–1600 Kcal/d for men to assure that status of other nutrients is not compromised.

TABLE 3.1 Example Recommended Calorie Intakes for Weight Reduction by Body Weight and Body Mass Indexa Body Weight (lb)(kg) 170–199 200–249 250–299 300–349 ≥ 350 a b

77–90 90–113 113–136 136–158 ≥ 158

BMI (kg/mb)b

Energy Intake Ranges (Kcal/d)

26–28 28–35 35–45 45–50 ≥ 50

1000–1200 1200–1500 1500–1800 1800–2000 2000

Table adapted from references 8, 25. BMI was calculated assuming a height of 5′8″.

48

Nutrition and Diabetes: Pathophysiology and Management

The optimal macronutrient (fat/protein/carbohydrate) distribution for weight reduction has not been resolved but is currently a matter of active debate (26). In recognition of the high caloric density of dietary fat and its relatively low satiety value compared to isocaloric amounts of carbohydrate and protein, a low-fat diet has been most typically employed for WR in diabetes, as well as in the general OW/OB population. However, the recent success of high-protein/high-fat/low-carbohydrate diets for WR has called this conventional approach into question. 3. Low-Fat Diets The accepted approach for the diabetic diet has generally included a relatively highcarbohydrate, low-fat (25 percent to 30 percent of Kcal from fat) distribution (27). While there are a variety of approaches to WR, this macronutrient distribution describes the conventional WR therapy for OW/OB. Randomized, controlled trials and other interventional studies of WR have found that decreasing dietary-fat intakes leads to decreased total energy intake and weight loss (28–30). Pirozzo et al. (31) systematically reviewed six randomized, controlled trials that compared a low-fat diet with another type of WR diet. The intervention and follow-up durations were 3–18 months and 6–18 months, respectively. The efficacy of low-fat diets was equal to but not greater than other WR diets with regards to sustained weight loss. However, only one of the six trials focused on subjects with type 2 diabetes (32). Very-lowfat diets have not been extensively studied but could be a concern because of the concomitant increase in carbohydrate intake that inevitably occurs when dietary-fat content is very low. High carbohydrate intakes could worsen lipid profiles by increasing triglycerides and lowering HDL cholesterol levels (33). 4. Low Carbohydrate and Other Nontraditional Dietary Approaches Among the general public, as well as those with type 2 diabetes, there has been a recent increased interest in the use of low-carbohydrate diets for OW/OB intervention. Klein et al. (8) summarizes five randomized trials in adults (34–38), comparing subjects assigned to a low-fat diet (~ 25 percent to 30 percent Kcal from fat and 55 percent to 60 percent Kcal from carbohydrate) to subjects randomly assigned to a low-carbohydrate, high-protein, high-fat diet (~ 25 percent to 40 percent of Kcal from carbohydrate). Subjects on the low-carbohydrate diet lost more weight in the short term (six months) but not the long term (12 months). In addition, glycemic control was found to be better (35, 37) and some serum lipids were improved. While these studies may offer promising dietary alternatives for those who are OW/OB, additional studies of long-term safety and efficacy are needed before low-carbohydrate diets are recommended as a WR strategy for OW/OB individuals with type 2 diabetes. Other dietary strategies may also offer promise. It has been recently suggested that a high-monounsaturated-fat diet would help avoid the risk of plasma triacylglycerol- and glucose-elevating effects of a high-carbohydrate diet, while still

Achieving a Healthy Body Weight

49

providing less saturated fat and cholesterol than a low-carbohydrate/high-fat regimen (27). 5. Comments on Overall Diet Composition Regardless of the approach for creating a dietary energy deficit, in the case of WR for individuals with type 2 diabetes, the advice of a nutritionist/registered dietitian should be sought for the design and individualization of the dietary plan. In these patients, maintenance of a healthy body mass may require long-term calorie restriction to some degree even for weight maintenance. So, it is important that the diet plan does not limit the intakes of essential nutrients (e.g., protein, vitamins, minerals) and that the diet provides a wide variety of nutritious foods in the long term. Any need for nutritional supplements (e.g., vitamins or minerals not consumed at adequate levels from the diet) should also be identified at this point. A diet history or typical diet record or recall may be collected to provide a profile of the usual intake and food preferences so that these can be taken into account in the diet plan whenever possible. Noting the need for individualization of dietary approaches, the joint recommendation of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition for type 2 diabetic patients needing to lose weight is to achieve a 500–1000 Kcal/d energy deficit and to choose a dietary intake pattern that is consistent with current recommendations to ameliorate comorbidities associated with obesity (8). A summary of other dietary recommendations to enhance overall health and minimize CVD risk includes the following: Saturated fat: Limit to less than 10 percent of total Kcal per day Cholesterol: Limit to ≤ 300 mg/day Fiber: Consume 20–35 g/day dietary fiber, both soluble and insoluble Sodium: If not hypertensive, sodium intake should be in the range of 2400–3000 mg/day Alcohol: Men, limit to two drinks/day; women, limit to one drink/day, consumed with food Vitamins and minerals: Insure adequate intakes from wide variety of dietary sources that meet recommended intake levels (Table 3.2).

B. EXERCISE INTERVENTIONS Programs for WR using dietary modification are more likely to succeed if physical activity is included as an integral component. Physical activity consumes calories and thus contributes to the energy deficit; it is particularly helpful for maintaining weight loss and preventing weight regain by providing motivation for long-term compliance with the diet (4, 40–42). It also promotes the selective preservation of lean body mass (LBM) during weight loss. Additional benefits that may accrue from regular physical activity include improved glycemic control, lowering of blood pressure, and a reduction in overall CVD risk (43). Specifically, it can lower the risk

2.4 2.4 2.4 2.4 2.4 2.4

1.3 1.5 1.5

Vitamin B12 μg) (μ

1.3 1.7 1.7

Vitamin B6 (mg)

1000 1200 1200

1000 1200 1200

Calciumc (mg)

320 320 320

420 420 420

Magnesium (mg)

18 8 8

8 8 8

Iron (mg)

8 8 8

11 11 11

Zinc (mg)

900 900 900

900 900 900

Copper μ) (μ

25 20 20

35 30 30

Chromium2 μg) (μ

55 55 55

55 55 55

Selenium μg) (μ

130 130 130 130 130 130

56 56 56 46 46 46

700 700 700

900 900 900 5 10 15

5 10 15 15 15 15

15 15 15 90 90 90

120 120 120

75 75 75

90 90 90

1.1 1.1 1.1

1.2 1.2 1.2

1.1 1.1 1.1

1.3 1.3 1.3

14 14 14

16 16 16

400 400 400

400 400 400

b

Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes, The National Academies Press, Washington, D.C., 2002–2003, 39. 0.80g/kg/day c Adequate Intakes (AIs) represent the recommended average daily intake level based on observed or experimentally determined approximations. AIs are used when there is insufficient information to determine an RDA.

a

Men 31–50 51–70 > 70 Women 31–50 51–70 > 70

Gender Proteinb Carbohydrate Vitamin A Vitamin Db Vitamin E Vitamin Kb Vitamin C Thiamin Riboflavin Niacin Folacin μg RAE) μg) μg) μg) Age (y) (g) (g) (μ (μ (mg) (μ (mg) (mg) (mg) (mg) (μ

Men 31–50 51–70 > 70 Women 31–50 51–70 > 70

Gender Age (y)

TABLE 3.2 Selected Dietary Reference Intakes for Adults Aged ≥ 31 Yearsa

50 Nutrition and Diabetes: Pathophysiology and Management

Achieving a Healthy Body Weight

51

of developing type 2 diabetes (44) and improve mortality in individuals with the disease (45). 1. Aerobic Exercise Aerobic exercise contributes to the energy deficit, improves cardiovascular fitness and lipid profiles, and also enhances the preservation of LBM and bone-mineral density. This benefit accrues for individuals with type 2 diabetes, as well as the general OW/OB population. Before embarking on an exercise program, OW/OB individuals with type 2 diabetes should be assessed as to the need for exercise stress testing (46), according to the discretion of their primary-care physician. Once readiness for training has been confirmed, a program of 30–45 minutes of moderate-intensity aerobic activity (40 percent to 60 percent maximum oxygen uptake or 50 percent to 70 percent maximum heart rate) three to five days per week is typically recommended with a gradual increase in duration and frequency of the activity (8, 47). For sedentary individuals who are quite inactive at the onset, the initial exercise should be of short duration and allow for a gradual progression to the target duration and intensity. 2. Resistance training Strengthening exercise (achieved through resistance training; RT) is known to increase muscle mass and strength and thus contributes to the preservation of these attributes during WR dieting. Moreover, RT improves a number of metabolic factors, especially insulin sensitivity. RT improves insulin action (48–51) whether measured by reduced insulin response to an oral-glucose tolerance test or with the euglycemic, hyperinsulinemic clamp. In fact, improved insulin sensitivity is one of the most important benefits of strength training. Castaneda et al. (52) have demonstrated this in adults with type 2 diabetes in only 16 weeks, and Wiley and Singh (53) note that RT can improve insulin sensitivity and glycemic control in elderly patients with diabetes. A typical training regimen might be calibrated to the one-repetition maximum (1 RM), the greatest resistance that can be safely moved in one repetition of a given exercise. An individual might begin with 8–12 repetitions at ~ 75 percent of this amount, which can be varied based on individual needs, preferences, and safety. An initial warm-up series of 8–12 repetitions at ≤ 50 percent of the 1 RM might then proceed with several sets of 70 percent 1 RM directed to target muscles and muscle groups. Resistance can be applied with free weights, cuff weights, exercise machines, or with differential grades of resistance using elastic therapeutic bands. A reasonably comprehensive program might include exercise to quadriceps, hamstrings, hip abductors and adductors, gluteals, calf muscles, pectorals, triceps, deltoids, latissimus dorsi, biceps, abdominals, and erector spinae (46). Exercise regimens can be gradually adjusted and recalibrated to the 1 RM as strength gains are noted. In addition, variations in the program can be incorporated by altering the number of sets or repetitions, the frequency or length of rest periods,

52

Nutrition and Diabetes: Pathophysiology and Management

or by incorporating the use of lighter weights (≤ 50 percent) with shorter rest periods between sets (sometimes referred to as circuit training). 3. Combination Training Ideally, for the joint purposes of enhancing weight reduction, preserving and possibly building lean mass, and improving cardiovascular and metabolic parameters, an optimal exercise regimen should incorporate a mixture of aerobic and resistance training, as the two types of exercise might have separate and different, as well as interactive, protective effects for the individual with type 2 diabetes. An exercise regimen might, for example, include some form of aerobic exercise three times weekly, supplemented by resistance training twice per week.

IV. CONCLUDING COMMENTS ON MAINTENANCE OF WEIGHT LOSS AND IMPROVED FITNESS Specific recommendations for weight-loss interventions for individuals with type 2 diabetes and OW/OB are summarized in Table 3.3. But it is recognized that for individuals who are OW/OB, achieving and maintaining an optimal body mass can be an uphill battle even in the absence of type 2 diabetes complications. While some patients are successful in maintaining at least some of their weight-loss achievement in the long term (54), dietary recidivism seems to be the rule rather than the exception. Thus, while many different dietary schemes show good success in the short term, most OB patients are unable to fully maintain their lower body weights in the long term. As an additional challenge, OB patients who have type 2 diabetes may be more resistant to the maintenance of weight loss because antidiabetic drugs, such as insulin and sulfonylurea, often promote weight gain. The progressive nature of diabetes means that even with successful monotherapy (e.g., management by diet/weight loss) glycemic control may deteriorate over time, necessitating the addition of

TABLE 3.3 Recommendations for OW/OB Individuals with Type 2 Diabetes and Those At Risk for the Disease 1.

2.

3. 4.

Weight loss is recommended for all those with type 2 diabetes mellitus whose BMI exceeds 25 kg/m2; the intervention strategy should include a reduced calorie intake and increased physical activity. The target BMI for this population is 25 kg/m2 or less; but even a modest weight loss of 5 percent to 10 percent of initial body mass will help prevent the development of diabetes and enhance metabolic control for those in whom the disease is already established. In most cases, a calorie-restricted diet should include no fewer than 1000 Kcal/day for women and 1200 Kcal/day for men. A program of regular, moderate-intensity exercise, including both aerobic exercise and resistance training, should be employed and maintained in order to preserve and increase lean-muscle mass, to assist long-term weight management, and to decrease the risk of CVD.

Achieving a Healthy Body Weight

53

pharmacologic treatments, including insulin (20), as discussed in the chpater by Lien and Feinglos in Section II of this book. In patients with longstanding disease or pronounced pancreatic β-cell dysfunction, moderate weight loss may not be sufficient to achieve satisfactory glycemic control. There may be a need for more intensive, ongoing intervention, including an escalation of calorie restriction to a very low-calorie diet, e.g., 800 Kcal/day or less (4, 55). In this event, a routine vitamin/mineral supplement and routine nutritional monitoring should be employed, and indications of medical complications, including gallstones (56), should be monitored. Weight-loss-promoting medications may need to be considered in some cases when calorie reduction and exercise do not result in sufficient weight loss, i.e., BMI ≥ 30 or BMI ≥ 27 plus OW/OB-related comorbid conditions. Bariatric surgery may be considered with a BMI ≥ 40 or BMI ≥ 35 plus comorbid conditions (47). Achieving a healthy body weight can be a daunting task for OW/OB individuals with type 2 diabetes, requiring encouragement and guidance from the health-care team and strong social support from family and friends. Invariably, the potential benefits are nothing short of remarkable, having few negative side effects and providing a number of indirect benefits (improved self-esteem, sense of control) in addition to wide-ranging improvements in health and mortality. Even if pharmacologic agents are needed to achieve full glycemic control, lifestyle interventions can help minimize necessary doses and maximize health benefits.

REFERENCES 1. Sturm, R, The effects of obesity, smoking, and drinking on medical problems and costs. Obesity outranks both smoking and drinking in its deleterious effects on health and health costs, Health Aff., 21, 245, 2002. 2. Mokdad, AH, et al., The continuing epidemics of obesity and diabetes in the United States, J. Am. Med. Assoc., 286, 1195, 2001. 3. Must, A, et al., The disease burden associated with overweight and obesity, J. Am. Med. Assoc., 282, 1523, 1999. 4. Tremble JM and Donaldson, D, Is continued weight gain inevitable in type 2 diabetes mellitus? J. R. Soc. Health 119, 235, 1999. 5. Campbell, L and Rossner, S, Management of obesity in patients with Type 2 diabetes, Diab. Med., 18, 345, 2001. 6. Astrup, A and Finer, N, Refining Type 2 diabetes: ‘diabesity’ or ‘obesity dependent diabetes melllitus’? Obesity Rev., 1, 57, 2000. 7. Yki-Jarvinen, H, Ryysy, L, Kauppila, M, et al., Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus, J. Clin. Endocrinol. Metab., 82, 4037, 1997. 8. Klein S, Sheard, NF, Pi-Sunyer X, et al., Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies. A statement of American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition, Am. J. Clin. Nutr., 80, 257, 2004. 9. Leung, WY, et al., Weight management and current options in pharmacotherapy: orlistat and sibutramine, Clin. Ther., 25, 58, 2003.

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Nutrition and Diabetes: Pathophysiology and Management 10. Brolin, RE, Bariatric surgery and long-term control of morbid obesity, JAMA, 288, 2793, 2002. 11. Field, AE, et al., Impact of overweight on the risk of developing common chronic diseases during a 10-year period, Arch. Intern. Med., 161, 1581, 2001. 12. Flegal, KM, Carroll, MD, Ogden, CL, and Johnson, CL, Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA 288,1723-1727, 2002. 13. Greene, GW, et al., Dietary applications of the stages of change model, J. Am. Diet. Assoc., 99, 673, 1999. 14. Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346, 393, 2002. 15. Tuomilehto J, Lindstrom J, Eriksson, JG, et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N. Engl. J. Med., 344, 1343, 2001. 16. Maggio, CA and Pi-Sunyer, FX, The prevention and treatment of obesity. Application to type 2 diabetes, Diabet. Care, 20, 1744, 1997. 17. Anderson, JW, et al., Carbohydrate and fiber recommendations for individuals with diabetes: a quantitative assessment and meta-analysis of the evidence, J. Am. Coll. Nutr., 23, 5, 2004. 18. Hanefeld, M and Sachese, G, The effects of orlistat on body weight and glycemic control in overweight patients with type 2 diabetes: a randomized placebo-controlled trial, Diabet. Obes. Metab., 4, 415, 2002. 19. UKPDS Group, UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, Metabolism, 39, 905, 1990. 20. Albu, K and Raja-Khan, N, The management of the obese diabetic patient, Primary Care, 30, 465, 2003. 21. Vidal, J, Updated review on the benefits of weight loss, Int. J. Obes. Relat. Metab. Disord., 26 (Suppl.), S525, 2002. 22. Anderson, JW and Kona, EC, Obesity and disease management: effects of weight loss on co-morbid conditions, Obes. Res., 9 (Suppl.), 326S, 2001. 23. Harris, J and Benedict, F, A biometric study of basal metabolism in man, Carnegie Institution, Washington, D.C., 1919. 24. Food and Nutrition Board, Institute of Medicine, Energy, in Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein and Amino Acids (Macronutrients), The National Academies Press, Washington, D.C., 149, 2002. 25. Klein, S, Wadden, T, and Sugarman, HJ, AGA technical review on obesity, Gastroenterology, 123, 882, 2002. 26. Astrup A, Meinert Larse T, and Harpe A, Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss? Lancet, 364, 897, 2004. 27. Garg, A, High-monounsaturated-fat diets for patients with diabetes mellitus: a metaanalysis, Am. J. Clin. Nutr., 67, 577S, 1998. 28. Wing, RR and Jeffery, RW, Food provision as a strategy to promote weight loss, Obes. Res., 9, 271S, 2001. 29. Yu-Poth, S, et al., Effects of the National Cholesterol Education Program’s Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis, Am. J. Clin. Nutr., 69, 632, 1999. 30. Saris, WH, Astrup, A, Prentice, AM, et al., Randomized controlled trial of changes in dietary carbohydrate/fat ratio and simple vs complex carbohydrates on body weight and blood lipids: the CARMEN study. The Carbohydrate Ratio Management in European National diets, Int. J. Obes. Relat. Metab. Disord., 24, 1310, 2000.

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31. Pirozzo, S, Summerbell, C, Cameron, C, and Glasziou, P, Should we recommend low-fat diets for obesity? Obes. Rev., 4, 83, 2003. 32. Pascale, RW, Wing, RR, Butler, BA, et al., Effects of a behavioral weight loss program stressing calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of diabetes. Diabet. Care, 18, 124, 1995. 33. Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus, JAMA, 271, 1421, 1994. 34. Foster, GD, Wyatt, HR, Hill, JO, et al., A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348, 2082, 2003. 35. Samaha, FF, Iqbal, N, Seshadri P, et al., A low-carbohydrate as compared with a lowfat diet in severe obesity, N. Engl. J. Med., 348, 2074, 2003. 36. Brehm, BJ, Seely, RJ, Daniels, SR, et al., A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women, J. Clin. Endocrinol. Metab., 88, 1617, 2003. 37. Stern, L, Iqbal, N, Seshadri, P, et al., The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one year follow-up of a randomized trial, Ann. Intern. Med., 140, 778, 2004. 38. Yancy, WS, Jr., Olsen, MK, Guyton, JR, et al., A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial, Ann. Intern. Med., 140, 769, 2004. 39. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes, The National Academies Press, Washington, D.C., 1–7, 2002–2003. 40. NIH, NHLBI, and North American Association for the Study of Obesity, The practical guide. Identification, evaluation, and treatment of overweight and obesity in adults, NIH, Bethesda, MD, 2000. 41. Wing, R. and Hill, JO, Successful weight loss maintenance, Ann. Rev. Nutr., 21, 323, 2001. 42. Doucet, E, Imbeaul, P, Almeras, N, and Tremblay, A, Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced–obese individual following weight loss by therapy and energy restriction? Obes. Res., 7, 323, 1999. 43. Stetson, B and Mokshagundam, SP, Nutrition and lifestyle change in older adults with diabetes mellitus, in Handbook of Clinical Nutrition and Aging, Bales, CW and Ritchie, CS, Eds., Humana Press, Totowa, NJ, 2004, chap. 21. 44. Wei, M, et al., The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men, Ann. Intern. Med., 130, 89, 1999. 45. Church, TS, et al., Exercise capacity and body composition as predictors of mortality among men with diabetes, Diabet. Care, 27, 83, 2004. 46. ACSM, American College of Sports Medicine Position Stand on the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness and flexibility in healthy adults, Med. Sci. Sports Exercise, 30, 975, 1998. 47. National Institutes of Health, NHLBI, and NIDDK, Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults, NIH, Bethesda, MD, 1998. 48. Miller, WJ, Sherman, WM, and Ivy, JL, Effect of strength training on glucose tolerance and post-glucose insulin response, Med. Sci. Sports Exercise, 16, 539, 1984. 49. Dunstan, DW, Daly, RM, Owen, N, et al., High-intensity resistance training improves glycemic control in older patients with type 2 diabetes, Diabet, Care, 25, 1729, 2002. 50. Eriksson, JG, Exercise and the treatment of type 2 diabetes mellitus, Sports Med., 27, 381, 1999.

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Nutrition and Diabetes: Pathophysiology and Management 51. Rice, B, Janssen, I, Hudson, R, et al., Effects of aerobic or resistance exercise and/or diet on glucose tolerance and plasma insulin levels in obese men, Diabet. Care, 22, 684, 1999. 52. Castaneda, C, Layne, JE, Munoz-Orians, L, et al., A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes, Diabet. Care, 25, 2335, 2002. 53. Wiley, KA and Singh, MA, Battling insulin resistance in elderly obese people with type 2 diabetes: bring on the heavy weights, Diabet. Care, 26,1580, 2003. 54. Wing, RR, Behavioral interventions for obesity: recognizing our progress and future challenges, Obes. Res., 11 (Suppl.), 3S, 2003. 55. Dhindsa, P, Scott, AR, and Donnelly, R, Metabolic and cardiovascular effects of verylow-calorie diet therapy in obese patients with Type 2 diabetes in secondary failure: outcomes after 1 year, Diabetic Med., 20, 319, 2003. 56. Weinsier, RL, Wilson, LJ, and Lee J, Medically safe rate of weight loss for the treatment of obesity: A guideline based on risk of gallstone formation, Am. J. Med., 98, 115, 1995.

4

Metabolic Syndrome: Recognition, Etiology, and Physical Fitness as a Component William E. Kraus, M.D. and Cris A. Slentz, Ph.D.

CONTENTS I . The Metabolic Syndrome ............................................................................57 II. Overview of Current Controversies with Definition of the Metabolic Syndrome ......................................................................................58 III. Cross-Sectional Studies of the Importance of Physical Fitness and Exercise to the Diagnosis and Etiology of Metabolic Syndrome..........60 IV. Metabolic Syndrome and Exercise..............................................................63 V. Exercise Training and Individual Components of Metabolic Syndrome ...64 A. Exercise-Training Effects on Blood Pressure.....................................64 B. Exercise-Training Effects on Triglycerides ........................................66 C. Exercise-Training Effects on HDL Cholesterol..................................66 D. Exercise-Training Effects on Fasting Plasma Glucose.......................67 E. Exercise-Training Effects on Insulin Sensitivity ................................69 F. Exercise Training Effects on Waist Circumference............................70 VI. Rationale for Including Cardiorespiratory Fitness in Metabolic Syndrome ......................................................................................71 VII. Future Directions for Research ...................................................................73 References................................................................................................................73

I. THE METABOLIC SYNDROME The general concept of the metabolic syndrome, which describes a clustering of metabolic abnormalities associated with increased risk of cardiovascular disease, diabetes, and hypertension, has been recognized for many years.1–4 Despite a definition of syndrome by the World Health Organization (WHO)5, the most commonly used definition is relatively new. In 2002, the National Cholesterol Education Program, in its Adult Treatment Program III (ATP III),6 presented a definition of 57

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metabolic syndrome that is commonly accepted in the U.S as a working model of the condition. However, the relative novelty of the condition to the general medical and lay audiences and only recent acceptance of a working definition means that there have been few studies of the prevalence, incidence, and response of metabolic syndrome to commonly available lifestyle interventions, such as exercise training. Several excellent reviews of metabolic syndrome exist.7–10 Hence, rather than presenting yet again a review of the topic of metabolic syndrome, in this chapter we will discuss several controversies that continue to plague the field and provide compelling lines of evidence that establish the strong relation between the metabolic syndrome, physical activity, and regular exercise. First, we will present evidence from cross-sectional studies that have consistently reported significant, inverse associations between levels of cardiorespiratory fitness or physical activity and the prevalence of metabolic syndrome (as defined in the ATP III report). Second, we will review the only published study of which we are aware that has analyzed (in a post hoc manner) the effect of exercise training on the metabolic syndrome as currently defined.11 Third, we will briefly present evidence of the relationship between exercise and physical activity and each of the five individual components of the metabolic syndrome. In the course of this discussion, several areas of controversy will become apparent. Where possible, we primarily will point to results from meta-analyses (e.g., blood pressure and exercise). Alternatively, we will reference expert review articles when meta-analyses are not available. In some cases we also discuss data from some key individual studies, relying more heavily on data from randomized, controlled trials (RCTs).

II. OVERVIEW OF CURRENT CONTROVERSIES WITH DEFINITION OF THE METABOLIC SYNDROME The current diagnostic criteria for metabolic syndrome are detailed in Table 4.1. Although the current ATP III definition provides a useful and accessible formula for

TABLE 4.1 ATP III Criteria Risk Factor

Defining Level

Metabolic syndrome is diagnosed when three or more of the following are present. Waist circumference Men > 102 cm (> 40 inches) Women > 88 cm (> 35 inches) Triglycerides ≥ 150 mg/dL HDL cholesterol Men < 40 mg/dL Women < 50 mg/dL Blood pressure ≥ 130/ ≥ 85 mm Hg Fasting glucose ≥ 110 mg/dL

Metabolic Syndrome

59

diagnostic purposes, it is not clear that it has much predictive capacity, thus limiting its clinical utility. Most consider metabolic syndrome to be a prediabetic state, as the various components of the condition are invariably associated with some degree of insulin resistance. However, there are relatively little to no definitive data on the conversion rate of individuals with metabolic syndrome to frank diabetes. Also, although the ATP III guidelines provide a useful working definition, it is clear that the five diagnostic criteria are not independent. For example, low-serum HDL cholesterol and high-serum triglycerides tend to track together in individuals. This makes the current scoring mechanism (i.e., the need to have three of the five diagnostic criteria) seem somewhat artificial and negatively impacts its predictive utility. Thus, there is room for further refining the clinical definition of metabolic syndrome. One potential improvement would be to provide differential weighting of the individual diagnostic conditions by providing a scoring system that incorporates the relative predictive capacity for future events or conversion to diabetes of the various components. Another would be to refine the predictive capacity through inclusion of additional diagnostic criteria, such as elevated high-sensitivity C-reactive protein (hsCRP), or, as we argue further on, through an assessment of cardiorespiratory fitness. There are other, less obvious issues with the current definition. The ATP III and WHO (Tables 4.1 and 4.2) include elevated blood pressure as part of the diagnostic criteria. Although most would agree that elevated waist circumference, fasting serum glucose, low-serum HDL cholesterol, and high-serum triglycerides tend to all be a

TABLE 4.2 WHO Criteria Risk Factor

Defining Level

Metabolic syndrome is diagnosed when the individual has: diabetes, IFG, IGT, or HOMAa insulin resistance AND AT LEAST TWO of the following: Waist-to-Hip Ratio Men Women Triglycerides HDL Men Women Urinary albumin excretion rate Blood pressure a

> 0.90 > 0.85 ≥ 150 mg/dL < 35 mg/dL < 39 mg/dL > 20 μg/min ≥ 140/90 mm Hg

IFG — impaired fasting glucose; IGT – impaired glucose tolerance; HOMA [resting determination of insulin sensitivity = (fasting glucose × 0.055551) × (fasting insulin/22.1)].

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Nutrition and Diabetes: Pathophysiology and Management

part of the same metabolic substrate for insulin resistance and diabetes mellitus, this is less clear for hypertension. More specifically, it is not apparent whether hypertension is another relatively common cardiovascular risk factor that tends to occur more frequently than not with other relatively common risk factors (associated with the prediabetic state) or whether, in fact, it is part of a metabolic substrate that is characteristic of individuals on the path to developing diabetes. When all five criteria are considered, we and others have noticed that there are striking differences in the prevalence of qualifying criteria among individuals of difference ethnicities. For example, in African Americans, hypertension is more likely to be a qualifying criterion than it is in Caucasians. Conversely, in Caucasians, lipid abnormalities predominate (studies of targeted risk reduction interventions through defined exercise [STRRIDE] data; Table 4.3).12,13 Waist-circumference measures, although attempting to account for differences in women and men, clearly do not account for other differences in body habitus that might influence the normalization of this measure. For example, should a waist circumference of 92 cm be equally applicable in a woman that is 152 cm (60 in) tall as it is in a woman that is 183 cm (72 in) tall? Further, gender differences can be striking in the contribution of waist circumference to metabolic abnormalities. We have observed that women have less visceral fat (unpublished data), lower triglycerides, and much lower serum concentrations of small dense atherogenic low-density LDL cholesterol than do men, even given similar waist circumferences (STRRIDE data; Table 4.3).12 Similar observations can be made for African Americans when compared with Caucasians, i.e., at nearly identical waist circumferences, African Americans have lower visceral fat (unpublished observations) and lower triglycerides compared to Caucasians. Thus, more precision may be achievable in the diagnosis of metabolic syndrome if the criteria were differentially weighted by height, gender, and ethnicity. Finally, as we will argue, there are likely other measures, relatively easily obtained clinically, that contribute to the clinical picture of insulin resistance and may be mechanistically involved in its etiology. These include cardiorespiratory fitness, (e.g., time to exhaustion on a maximal treadmill exercise test) and concentrations of specific lipoprotein subspecies, such as small dense LDL cholesterol.

III. CROSS-SECTIONAL STUDIES OF THE IMPORTANCE OF PHYSICAL FITNESS AND EXERCISE TO THE DIAGNOSIS AND ETIOLOGY OF METABOLIC SYNDROME Cross-sectional studies have consistently found that higher levels of cardiorespiratory fitness or physical activity are associated with decreased risk of morbidity and mortality from diabetes,14,15 cardiovascular disease,16,17 hypertension,18,19 cancer,16 and metabolic syndrome.20,21 In 1999, data from the Aerobics Center Longitudinal Study (ACLS) of the Cooper Clinic in Dallas, Texas, were analyzed for the relationship between cardiorespiratory fitness and metabolic syndrome.20 This study was published before the ATP III definition of metabolic syndrome was available and, as a result, it used a slightly different definition of metabolic syndrome. In this study,

143 49.8 16.9 42.3 46.0 ± ± ± ± ±

± + ± ± ± ± ± 80.8 11.1 11.5 29.0 64.8

25.3 0.78 326 31.2 34.8 45.0 5.75

± 12.4 ± 0.36 ± 5.09 ± 13.5

112 47.4 20.0 35.9 22.5

124 21.0 1345 16.2 50.3 56.1 1.59

37.8 ± 11.9 8.67 ± 0.34 19.8 ± 4.87 18.0 ± 13.0

185 ± 30.5

± ± ± ± ±

75.8 10.4 10.8 27.2 60.7

176 53.9 18.3 50.5 71.2

± ± ± ± ±

77.4 10.6 11.0 27.8 62.0

± 23.8 121 ± 24.3 + 0.73 20.5 + 0.75 ± 305 1414 ± 312 ± 29.3 34.7 ± 29.9 ± 32.6 41.9 ± 33.3 ± 42.2 40.1 ± 43.0 ± 5.40 3.91 ± 5.51

42.4 ± 11.6 8.90 ± 0.33 19.3 ± 4.78 23.1 ± 12.6

187 ± 29.9 .0001 .0001 .0001 .0001

0.0002 0.0019 0.2107 0.0121 0.0006

0.0074 < .0001 0.0634 <.0001 0.0034 <.0001 0.9585

< < < <

< .0001

M> F M> F

M> F M> F

F> M F> M M> F M> F M> F F> M

F> M F> M M> F F> M

F>M

< .0001 < .0001 0.5084 0.0001 < .0001

0.7239 0.0022 0.0557 0.0112 0.5438 0.0212 < .0001

0.1855 0.0004 0.8559 0.2034

0.2466

Race Difference

W> B W> B

W> B W>B

B> W W> B

B>W W> B W> B

B> W

Note: Data expressed as adjusted mean ± SD; Data determined by analysis of covariance adjusting for differences in age and BMI; No interactions between gender and race were observed; ‡ ANCOVA performed using ranked data.

77.9 10.7 11.1 28.0 62.5

Trilyceride (mg/dL) ‡ VLDL size (nm) Small VLDL (mg/dL Tg) Medium VLDL (mg/dL Tg) Large VLDL (mg/dL Tg) ‡ ± ± ± ± ±

131 21.2 1351 14.3 35.0 78.1 3.70

LDL-C (mg/dL) 126 ± 24.4 LDL size (nm) 21.4 + 0.75 LDL particle (nmol/L) 1250 ± 314 Small LDL (mg/dL Chol) ‡ 8.50 ± 30.1 Medium LDL (mg/dL Chol) ‡ 30.1 ± 33.5 Large LDL (mg/dL Chol) ‡ 85.9 ± 43.4 IDL (mg/dL Chol) ‡ 1.08 ± 5.55 85.7 43.6 17.4 26.0 5.98

52.8 9.05 17.1 35.7

207 ± 31.9

12.0 0.34 4.91 13.0

53.0 9.17 17.3 35.6

HDL-C (mg/dL) HDL size (nm) Small HDL (mg/dL Chol) Large HDL (mg/dL Chol) ± ± ± ±

195 ± 30.8

Cholesterol (mg/dL)

Black Women White Women Black Men White Men Gender n = 40 n = 108 n = 29 n =1 08 Difference

TABLE 4.3 Lipoprotein Subclass Distributions by Group and Gender/Race Statistical Comparisons

Metabolic Syndrome 61

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the variables associated with insulin resistance identified by Kaplan22 as part of the “deadly quartet” included systolic BP (≥ 140 mmHg), hypertriglyceridemia (≥ 150 mg/dl), hyperglycemia (fasting glucose ≥ 110 mg/dl), and central adiposity (waist circumference ≥ 100 cm for both men and women). They did not include HDL cholesterol in this study due to its strong correlation with TG. A total of 15,534 men and 3898 women were included in the study. Cardiorespiratory fitness was assessed by time to exhaustion on a treadmill-exercise test, and fitness categories were based on age and gender-normative data. Finally, the association between fitness and clustering of metabolic abnormalities was assessed using proportional odds logit models. For the men, the age-adjusted, cumulative-odds ratio for abnormal markers of metabolic syndrome was 10.1 (C.I. 9.1–11.2, P < 0.0001) when comparing the least-fit with the most-fit men, and was 3.0 (95 percent C.I. 2.7–3.4; P < 0.0001) when comparing the least fit with the moderately fit. For women, the odds ratio was 4.9 (C.I. 3.8–6.3; P < 0.0001) when comparing the least-fit to the most-fit women, and was 2.7 (C.I. 2.7–3.4; P < 0.0001) when comparing the least fit to the moderately fit. These data provide very strong evidence that a highly significant relation exists between cardiorespiratory fitness and clustering of factors of the metabolic syndrome. In another study of the relationship between metabolic syndrome, physical activity and fitness by Carroll et al., 23 similar findings were reported. This study, only in men presenting for preventive assessment at a private hospital in the United Kingdom (n = 711), reported age-adjusted odds ratios for metabolic clustering of 0.28 (95 percent C.I., 0.14–0.57) for moderate fitness versus low fitness and 0.12 (95 percent C.I. 0.05–0.32) for high fitness versus low fitness (P < 0.0001). They also reported that even after exclusion of obesity in the metabolic syndrome definition, the relationship between cardiorespiratory fitness and metabolic syndrome was still significant. Similar relationships were observed for physical-activity measures obtained via recall questionnaire. The confidence level for a trend between physical activity and metabolic syndrome was less (P < 0.05) than it was for cardiorespiratory fitness and metabolic syndrome (P < 0.0001). This is likely due to the nature of the measure, as physical-activity questionnaires are inherently less accurate than the more highly reproducible time to exhaustion on an exercise test. More recently, Irwin et al. 24 examined the relationships between fitness and metabolic syndrome in a smaller sample of women of three ethnicities (African American, n = 49; Native American, n = 46; and Caucasian, n = 51). In this study, the current ATP III definition for metabolic syndrome was used. Physical activity was determined prospectively from detailed subject records that included all physical activity performed during two consecutive four-day periods. Cardiorespiratory fitness was determined from maximal treadmill time during a graded exercise test. They reported significant inverse relations between metabolic syndrome and higher levels of moderate-intensity physical activity (P < 0.01), vigorous-intensity physical activity (P < 0.01), and maximal treadmill time (P < 0.0004) among an ethnically diverse population of women. This appears to be the first study of these relationships in minority women. Importantly, they found that while all associations were statistically significant, the strongest association was between metabolic syndrome and maximal treadmill time. They suggested that cardiorespiratory fitness was a more

Metabolic Syndrome

63

objective, albeit indirect, measure of physical activity, and as such is a more accurate exposure variable. It is important to note that physical activity records are generally a reflection of recent activity levels, whereas cardiorespiratory fitness likely reflects a much longer-term effect of regular habitual physical activity. Highlighting the consistency and generalizability of the relationship between physical activity, cardiorespiratory fitness, and metabolic syndrome are similar data reported by Lakka et al. 25 in Finnish men, and by Panagiotakos et al.26 in Greek men and women. In the Lakka study, the relationship between physical activity and metabolic syndrome and between cardiorespiratory fitness and metabolic syndrome was significant, and the magnitude and level of significance was once again much greater for the relation between cardiorespiratory fitness and metabolic syndrome than for physical activity and metabolic syndrome. In fact, total leisure-time physical activity was found to be significantly related to metabolic syndrome when adjusted for age only, or for age and multiple other factors (P < 0.03). Neither low-intensity physical activity nor moderate and vigorous physical activity was significantly related with metabolic syndrome using either statistical model. However, cardiorespiratory fitness was inversely related to metabolic syndrome (P < 0.001) for both the age-adjusted model and for the model that adjusted for age, smoking, alcohol consumption, and socioeconomic status. They found that the least-fit men were almost seven times more likely to have the metabolic syndrome than the most-fit men even when major confounders were controlled. Furthermore, Lakka found, even after controlling for body-mass index, that the least-fit men had a nearly fourfold likelihood of having the metabolic syndrome when compared with the most-fit men, suggesting a strong, independent relationship between cardiorespiratory fitness and prevalence of metabolic syndrome. The observation that cardiorespiratory fitness independent of body-mass index is a very strong predictor of metabolic risk, diabetes risk, and overall cardiovascular risk is supported by numerous studies from the Aerobics Center Longitudinal Study of Dallas.27-30 In aggregate, these findings imply that cardiorespiratory fitness should be included as a defining variable of the metabolic syndrome. In fact, one of the conclusions of Lakka et al.25 was that the measurement of peak oxygen consumption (VO2) (a measure highly correlated with time to exhaustion in an exercise test) in sedentary men with cardiovascular risk factors might provide an efficient means for targeting individuals who would benefit from interventions to prevent the metabolic syndrome and its consequences. Presumably, these relationships hold as strongly in women as in men, although the data is not as extensive in women.

IV. METABOLIC SYNDROME AND EXERCISE The relatively recent recognition of the metabolic syndrome as a clinically definable entity implies that few studies are available that address the specific effects of exercise training on the prevalence of metabolic syndrome. To our knowledge, there is only one exercise-training study that has published data analyzed (post hoc) based on the new ATP III definition of metabolic syndrome. This study is the Heritage Family Study11. The Heritage Family Study was a multicenter study, including a large number of individuals across a large age range (18–65 yr) in African American and Caucasian men

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and women. Complete data were available on 621 subjects who completed the exercise training. Of these, 105 had metabolic syndrome as defined by ATP III. The race and gender distribution coupled with the wide age range of study participants in this trial makes the findings likely generalizable to a large portion of the U.S. adult population. Furthermore, the research design emphasized close attention to the details of measurement and quality control within and between sites, strengthening the validity of the conclusions.31 Of pertinence, the exercise exposure was very carefully monitored and standardized with the data presented representing those individuals who completed 95 percent or more of the prescribed exercise sessions. In the Heritage Family Study, of the 105 subjects who had the ATP III definition of metabolic syndrome (waist circumference, fasting, triglycerides, HDL-C and glucose, and blood pressure), nearly one third (30.5 percent, 32 of the 105) were no longer defined as having metabolic syndrome after the exercise-training program of 20 weeks. This was a highly physiologically, clinically, and statistically significant effect. It is particularly impressive, given that the exercise stimulus was of a fairly modest weekly amount (likely very similar total amount of exercise as approximately 30 min of moderate-intensity exercise six days per week) and was of a relatively modest training duration. In Figure 4.1, the prevalence of individual risk factors and the prevalence of metabolic syndrome is shown with both before and after prevalence rates. Of the five risk factors, all except the prevalence of low HDL-C were significantly decreased with exercise training. In individuals with a clustering of metabolic syndrome risk factors (i.e., three or more risk factors), the prevalence of metabolic syndrome was even more substantially reduced with the exercise-training intervention than any of the individual risk factors. In Table 4.4, the prevalence percentages for each of the five risk factors are shown individually for each subject subgroup (black men, white men, black women, and white women). The consistency of the exercise effects on metabolic syndrome across race and gender subgroups and over a large range of ages emphasize, as did the previous cross-sectional studies, the strong generalizability of these effects.

V. EXERCISE TRAINING AND INDIVIDUAL COMPONENTS OF METABOLIC SYNDROME A discussion of the effects of individual exercise training studies on each of the five individual components of the metabolic syndrome is beyond the scope of this review. Instead, we will summarize the effects by briefly discussing reviews and metaanalyses, and in some cases a few key exercise training studies.

A. EXERCISE-TRAINING EFFECTS

ON

BLOOD PRESSURE

Numerous meta-analyses of the effect of aerobic exercise on blood pressure have been published, and the results have been consistent. Fagard18 performed a metaanalysis on 44 RCTs and concluded that aerobic exercise reduces blood pressure and that the lowering effect was greater in hypertensives (–7/–6 mm Hg) than normotensives (–3/–2 mm Hg). Further, he concluded that the evidence in support of these findings achieved the highest level of confidence rating, i.e., a “Category

Metabolic Syndrome

* * * *

%

100 90 80 70 60 50 40 30 20 10 0

65

*

High TG

Low HDL-C

High BP

High Glucose

Pre-Training

High WC

Metabolic Syndrome

Post-Training

FIGURE 4.1 Prevalence of individual risk factors before and after 20 wk of aerobic exercise training in the HERITAGE Family Study among 105 participants with the metabolic syndrome at baseline. *P < 0.05 pretraining versus posttraining. Reprinted with permission from Med. Sci. Sport Exerc., 35:1703–09, 2003.

TABLE 4.4 Prevelance (%) of Risk Factors Pre- and Post Training Among 105 Participants in the HERITAGE Family study Classified as Having the Metabolic Syndrome at Baseline High TG

Low HDL

High BP

High Glucose

High WC

Black men Pre 93 Post 79

100 100

71 43

43 29

43 43

White men Pre 76 Post 63

98 93

46 42

24 7

93 76

Black women Pre 26 Post 13

100 96

87 65

35 30

100 91

White women Pre 81 Post 62

100 93

26 22

15 19

100 93

A” level, indicating that the conclusion was based on a rich body of data from well-designed, randomized clinical trials providing a consistent pattern of results. In addition to this general finding, this report looked at the effects of the individual components of exercise training: intensity, frequency, and individual session duration. Fagard concluded that the beneficial aerobic-exercise effect was not dependent

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on exercise intensity (between 40 percent 70 percent of maximal exercise performance) and that the effect was similar for frequencies of three to five times per week and for session durations of 30–60 minutes. In a somewhat larger and more recent meta-analysis, also on RCTs (n = 54), Whelton et al.32 concluded that aerobic exercise decreased diastolic and systolic blood pressure in both hypertensive and normotensive individuals. The effect was somewhat larger in the hypertensives (–5/–4 mm Hg) than the normotensives (–4/–2 mm Hg). Additional analyses revealed that the beneficial exercise effects were observed in Caucasians and Asians for both systolic and diastolic blood-pressure reductions. In African Americans, a significant beneficial effect was found for systolic, but not diastolic, blood pressure. Importantly, only two studies met the analysis criteria and were included in the analysis for exercise effect and diastolic blood pressure in African Americans, suggesting the need for additional studies in minorities. Several other meta-analyses have been conducted over the years, and all have reported a significant exercise effect on blood pressure.32–35 In spite of the finding of a consistent, beneficial effect of exercise on blood pressure in numerous metaanalyses, important ethnic differences exist for health parameters in general, yet a relatively small number of studies of exercise and blood pressure were found in both African Americans and Asians. While no analysis was presented for the separate effects of exercise on blood pressure in women and men, seventeen of the fifty-one trials that reported sex distribution included predominantly women (≥ 80 percent), while only 10 were predominantly men.

B. EXERCISE-TRAINING EFFECTS

ON

TRIGLYCERIDES

One of the more extensive reviews of the effects of exercise on lipids and lipoproteins was conducted by Durstine and Haskell.36 First, in analyzing several cross-sectional studies comparing inactive controls to either endurance athletes, runners, crosscountry skiers, tennis players, or individuals with longer treadmill test times, they concluded that generally active individuals have lower triglyceride concentrations. With regard to exercise-training studies, they reported that training also generally reduced the triglyceride levels if the baselines were elevated. They also found that the degree of reduction in triglycerides was related to both the baseline amount of triglyceride elevation and to the volume of exercise training, but that in women, these findings were not as consistent. In a more recent meta-analysis of fifty-one studies, of which twenty-eight were randomized controlled trials, Leon and Sanchez37 reported an overall 3.7 percent average decrease in triglycerides (P < 0.05). They also reported that men generally had a greater reduction then women. However, in general, they concluded that the blood-lipid response to exercise, including the triglyceride response, was quite variable, confirming similar observations from previous reviewers.

C. EXERCISE-TRAINING EFFECTS

ON

HDL CHOLESTEROL

Durstine and Haskell36 reported that in cross-sectional studies endurance athletes have 20 percent to 30 percent higher levels of HDL cholesterol when compared to

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67

inactive controls. Cross-sectional studies also suggest a dose-response relationship between amount of exercise and HDL-C concentrations. However, exercise-training studies, according to Durstine and Haskell, have not been as consistent, as many studies have reported a significant training benefit on HDL-C levels, while many other studies did not find the effect to be significant. Leon and Sanchez,37 in their meta-analysis, reported a marked inconsistency of the effects of aerobic-exercise training on blood lipids in general, and they suggested that the most frequent finding was of a significant (P < 0.05) increase in HDL-C. However, this significant beneficial effect was reported in only 24 of the 51 studies (47 percent) included in the review. The exercise-induced change in HDL-C ranged from a decrease of 5.8 percent to an increase of 25 percent. Nevertheless, overall there was an average increase of 4.6 percent across the studies (P < 0.05). Some help in understanding the variability in the lipid response has recently been reported in an eight-month exercise training study by Kraus et al.38 In the first randomized controlled study of the effect of two different amounts of exercise training on HDL-C, they reported that only the larger amount of exercise (an amount of exercise calorically equivalent to ~ 17 miles of jogging per week) was found to have a significantly increased HDL-C, compared to an inactive control group. The two lower amounts of exercise training (both calorically equivalent to ~ 11 miles per week, one group at a moderate exercise intensity and the other group at a more vigorous exercise intensity) had small, nonsignificant, increases in HDL-C. Thus, the Kraus study confirmed the earlier analysis of Durstine and Haskell, which reported that cross-sectional studies suggested that there was a dose-response effect of exercise training on HDL-C improvement.

D. EXERCISE-TRAINING EFFECTS

ON

FASTING PLASMA GLUCOSE

In a recent meta-analysis of controlled clinical trials (11 randomized and three nonrandomized) on the effects of exercise training on glycemic control in individuals with type 2 diabetes, Boule and colleagues39 reported a significant (P < 0.001) beneficial exercise effect on glycosylated hemoglobin (HbA1c) (–0.66 percent) compared to the controls. The authors concluded that exercise training reduces HbA1c by an amount that should decrease the risk of diabetic complications. The difference found in this meta-analysis was close to the difference (–0.9 percent) between conventional and intensive glucose-lowering therapy reported in the United Kingdom Prospective Diabetes Study (UKPDS)40,41; an amount that was associated with significant improvement in clinical outcomes (development of microvascular and macrovascular complications of diabetes, including cardiovascular disease). The authors went on to speculate that exercise might result in a greater reduction in cardiovascular complications than with insulin or sulfonylureas since exercise has additional cardioprotective benefits and does not cause weight gain. We are not aware of a meta-analysis of the effects of exercise training in nondiabetics, most likely because HbA1c, a good, long-term measure of glucose control, is not often measured in nondiabetic subjects. Neither are we aware of a meta-analysis of the effects of exercise on fasting blood glucose in any population. There are a number of individual exercise studies in normal individuals that report

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fasting glucose11,42 and HbA1c43 are significantly improved with exercise training. Unfortunately, none of these studies had a control group. Additionally, there are many exercise-training studies in normal individuals where no decrease in fasting glucose is observed, presumably because these individuals already have normal and healthy fasting glucose levels44 (unpublished observations). In a comprehensive review by Ivy et al.,45 several lines of evidence are presented that support a key role of exercise and physical activity in prevention and treatment of diabetes. As diabetes is defined by fasting glucose, prevention of diabetes is defined by the prevention of increases in fasting serum glucose. Ivy and colleagues reviewed numerous epidemiological studies (cross-sectional, retrospective, and prospective designs) that provide strong support for the beneficial effect of physical activity in the prevention of type 2 diabetes. Studies on the population of Mauritius showed that the relationship between low levels of physical activity and increased prevalence of impaired fasting glucose and type 2 diabetes existed across both sexes and across the major ethnic groups on the island46–48 and that total physical activity was a significant, independent predictor even after controlling for several major confounders. Mayer-Davies et al.49 reported similar findings in a large, culturally and ethnically diverse sample of men and women. Kriska and colleagues reported the same relationship in Pima Indians.50 Manson et al.,51,52 in a prospective study, provided additional evidence of this relationship, including evidence of a doseresponse effect of increased exercise frequency and reduced risk of type 2 diabetes. Ivy et al. presented additional evidence in their review of bed-rest studies53–56 and exercise-detraining studies,57–59 which together revealed a rapid deterioration in insulin action and glucose tolerance (if the individual/population was glucose intolerant) with even short periods of bed rest or detraining. But, does exercise training improve glucose tolerance and prevent development of type 2 diabetes? Exercise training reliably improves insulin action in all subjects but does not affect glucose tolerance in normal individuals. However, in glucoseintolerant individuals, exercise does result in improvements in glucose tolerance. In a seven-day exercise-training study in ten men with mild type 2 diabetes or impaired glucose tolerance, Holloszy’s group60 found that two of three who had impaired glucose tolerance had a normal oral glucose-tolerance test after training. Of the seven men with type 2 diabetes, three had normal oral glucose-tolerance tests after training, two had only impaired fasting glucose, and two still had diabetic oral glucose-tolerance tests after seven days of training. The two who still had diabetic oral glucose-tolerance tests had relative hypoinsulinemia, whereas the other eight that improved with exercise all had mild to moderate hyperinsulinemia. The data suggest that when sufficient insulin reserve exists, exercise training has the potential to reverse glucose intolerance and even mild type 2 diabetes. Results from cross-sectional studies of young and old endurance athletes compared to young and old (lean and not lean) untrained individuals show that untrained individuals have decreased insulin action and decreased glucose tolerance compared to young and old athletes.61 The master athletes, compared to young athletes, had essentially identical insulin and glucose responses to an oral glucose-tolerance test, indicating that age need not result in impaired glucose tolerance. The authors suggested that earlier studies that had shown no improvement in insulin action or glucose

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tolerance generally used an insufficient exercise stimulus, waited too long after the final exercise bout, and used patients with relative insulin deficiency. When this group trained individuals for one year who were mildly diabetic without insulin deficiency and measured oral glucose-tolerance tests within 18 hours of the last bout of exercise, they found significantly improved glucose tolerance and insulin action and that fasting glucose levels were normalized.62 Data from Reitman et al.63 reported 6–10 weeks of intensive exercise lowered fasting glucose and improved glucose tolerance in obese type 2 diabetic individuals. Other studies in type 2 diabetic subjects support these findings.64,65 While the totality of the data are quite compelling, it is clear that a large, controlled, randomized study of the effects of exercise training in mild type 2 diabetic subjects would provide more definitive evidence for the potential reversal of type 2 diabetes with exercise training. One cannot discuss the effects of exercise training on progression to diabetes in individuals without mention of the results of the Diabetes Prevention Program.66 In this study, the effects of pharmacologic therapy (metformin) and lifestyle interventions (exercise training at the level of ACSM/CDC recommendations of 30 minutes per day most days of the week, diet, and weight loss for a total of 7 percent body weight) were compared with usual care. The results revealed that the lifestyle intervention reduced the risk of progression to diabetes in this population by 58 percent compared with usual care. The effects of metformin, although statistically and clinically significant, were less impressive in reducing rate of progression to diabetes, which it did by 31 percent compared to usual care. Granted, this trial did not study the effects of exercise alone, but it points out the utility of lifestyle interventions in individuals with metabolic syndrome.

E. EXERCISE-TRAINING EFFECTS

ON INSULIN

SENSITIVITY

The metabolic syndrome is conceptually the same as the insulin-resistance syndrome, and the names are essentially interchangeable. That some prefer the term insulin-resistance syndrome is due to the common understanding that an observable decrease in insulin sensitivity is the first detectable aberration in course toward metabolic syndrome. In fact, some deterioration in insulin sensitivity is generally observed prior to elevations in triglycerides levels, decreases in HDL-C concentrations, which in turn precede deterioration in fasting glucose, and glucose-tolerance measures, and perhaps even before clinically significant increases in body weight, body-mass index, and waist circumference are apparent. In fact, as a reflection of this understanding, the WHO includes a resting measure of insulin resistance in its definition of metabolic syndrome (Table 4.2). The relationship between exercise and insulin resistance is clear. In fact, one of the most consistent, beneficial effects of exercise is a statistically and physiologically significant improvement in insulin action. This beneficial effect can be observed in a broad range of exercise conditions and models: after only a few bouts of acute exercise,60,67 or with longer term exercise training68–71; with low-intensity or highintensity exercise (Figure 4.1 from Houmard et al., 200467,72); and in exercising animals71 and humans.68-70 In a classic study, Seals et al.61 observed that even young, lean, but sedentary individuals have nearly twice the insulin response to an

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* α

120

* α

100 Change SI (%)

80 60

*

40 20 0 –20

Control

Low/Mod Low/High High/High Group

FIGURE 4.2 Relative changes (%) (after training/before training) in insulin-sensitivity index derived from the intravenous glucosetolerance test (Si) in the control and exercise [lowvolume/moderate-intensity (Low/Mod); low-volume/high-intensity (Low/High); high-volume/high-intensity (High/High)] groups. Line at 0.0 represents no change. *Significant difference from control group, P < 0.05; Alpha symbol ó significant difference from the Low/Highgroup, P < 0.05. Reprinted with permission from J. Appl. Physiol., 96:101–106, 2004.

oral-glucose administration as young, lean, endurance athletes. Aging had no influence on this observation, as the results were the same when the young, lean, sedentary individuals were compared to older (mean age 60 years), lean, endurance athletes, demonstrating an improved insulin action in endurance athletes when compared with sedentary controls. In a study from our group,72 the data revealed that of the two groups performing the same amount of exercise (calorically equivalent to walking or jogging ~ 10 miles per week), the lower exercise-intensity group had a greater improvement in insulin sensitivity (Figure 4.2). This may specifically be due to a beneficial effect of low-intensity exercise, which is known to oxidize more fat than the same amount of more vigorous exercise. Alternatively, it may be due to the higher exercise frequency and total time of weekly exercise required by the low amount/moderate-intensity group to expend the same amount of calories through exercise. Whether this same observation holds for individuals with frank diabetes remains an open question and a potential area for future investigation.

F. EXERCISE TRAINING EFFECTS

ON

WAIST CIRCUMFERENCE

In randomized, controlled trials that provided a significant increase in exercise volume, either through a large, weekly amount of exercise for a short time period (4900 Kcal/wk for 12 weeks; Ross et al.44), or a smaller, weekly amount over a long time period (980 Kcal/wk for 48 weeks; Binder et al.73), or both (2000 Kcal/wk for 36 weeks; Slentz et al.74), statistically and physiologically significant decreases in waist circumference have been observed. In the randomized, controlled exercisetraining study by Kraus’ group,74 two amounts of exercise (low dose, ~ 1200 Kcal/wk, and high dose, ~ 2000 Kcal/wk) combined with a control (no extra Kcal/wk through exercise) revealed a clear, strong volume of exercise effect on reductions in abdominal obesity as measured by waist circumference (Figure 4.3). In this study,

Metabolic Syndrome

71

Δ Waist Cir (%)

2 0 –2 –4 –6

Control

Low-amount Low-amount High-amount moderate-intensity vigorous-intensity vigorous-intensity

FIGURE 4.3 Effects of exercise amount and intensity on mean percent changes in waist circumference. * Indicates P < 0.05 compared with controls. Error bars show SE.

even the low-dose exercise groups had significant reductions in waist circumference compared to the inactive control group. Clearly, when a significant exercise-training stimulus is provided, waist circumference and abdominal obesity are reduced.

VI. RATIONALE FOR INCLUDING CARDIORESPIRATORY FITNESS IN METABOLIC SYNDROME Lakka et al. suggested that a sedentary lifestyle and especially poor cardiorespiratory fitness are not only associated with metabolic syndrome but could be considered central, defining features of metabolic syndrome.25 Further, they suggested that measurement of peak VO2 in sedentary men with risk factors could provide a means of identifying individuals who would most benefit from interventions, especially lifestyle interventions, in individuals at risk of developing diabetes mellitus. Numerous studies have revealed a clear, independent relationship between exercise capacity (cardiorespiratory fitness) and cardiovascular events and all causes of deaths in men.16,17,75–82 And in a recent study by Gulati et al.,83 the authors reported a strong, independent relationship between exercise capacity as a predictor of death in asymptomatic women, which they observed was stronger than what had been previously established among men. Even after adjusting for traditional cardiovascular risk factors via the Framingham Risk Score (a point system assessing risk, which includes total cholesterol, HDL-C, age, systolic blood pressure, diastolic blood pressure, smoking, and the presence or absence of diabetes), they found that the adjusted hazards ratios (with 95 percent CI) of death associated with MET levels of < 5, 5 to 8, and > 8 were 3.1 (2.0 to 4.7), 1.9 (1.3 to 2.9), and 1.00, respectively. Data from the Cooper Clinic had revealed similar, albeit not as strong, relationships between cardiorespiratory fitness and cardiovascular disease mortality16 in women. Further, Weinsier et al.,84 using U.S. data, and Prentice and Jeb,85 using U.K. data, extensively reviewed the data concerning the question of whether the obesityand-diabetes epidemic is primarily due to overeating or lack of physical activity (the “gluttony versus sloth” debate). Both have cautiously concluded that, even given the

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difficulty in measuring changes in caloric consumption or physical activity over the past decades, it is clear that physical inactivity is a major culprit in the obesity epidemic. They go on to suggest that perhaps physical inactivity is the major culprit. This concept is supported by studies from the 50s in carefully performed studies in animals86 and humans.87 Meyers et al. observed that at significant physical activity levels, increases or decreases in physical activity were matched with increases or decreases in food intake. However, below certain minimal levels of physical activity, further decreases in physical activity were not met by further decreases in food intake, but rather by increases in food intake and consequent body weight. They interpreted the data to suggest that a minimal level of physical activity might be necessary for appropriate appetite control. Recent data from our group provides support for this theory. In our study,74 inactive controls gained weight over a sixmonth period, whereas two different low-dose exercise-training groups (equivalent to ~ 12 miles/wk of walking or jogging) lost weight and a higher dose (equivalent to ~ 17 mile/wk) lost even more body mass. The data suggest that below a certain level, appetite control is not appropriately balanced, and weight gain occurs. If these suggestions are correct, then the extreme levels of physical inactivity present in today’s society may be at the root of the obesity-and-diabetes epidemic in that these levels of inactivity may directly lead to the inability to balance food intake with decreasing physical-activity levels, resulting in continuous weight gain and progression from metabolic syndrome to diabetes. As reviewed previously, physical-activity levels are poorly measured, whereas cardiorespiratory fitness is a relatively easily measured, reliable, and accurate clinical assessment that is a good surrogate for physical activity. Studies show that both moderate and vigorous-intensity activity can lead to increases in cardiorespiratory fitness.38,88 Finally, in a particularly compelling article entitled “Exercise capacity: The prognostic variable that doesn’t get enough respect,” Mark and Lauer discuss what they refer to as “one of the most potent prognostic variables,”89 i.e., exercise capacity/cardiorespiratory fitness. The article is precipitated by the Gulati et al.83 study (see discussion above) reported in the same issue, along with numerous studies that have come before this. Mark and Lauer argue that the overwhelming amount of data support the role of exercise capacity as a potent prognostic indicator of future health for both men and women and for both symptomatic and asymptomatic individuals. We believe that the accumulated evidence provides strong rationale for including cardiorespiratory fitness as one of the major defining diagnostic components of the metabolic syndrome. Furthermore, by including cardiorespiratory fitness in the definition of metabolic syndrome, individuals and physicians would more likely focus directly on physical activity and fitness as measures of health. This would also demand attention to methods for increasing physical activity and cardiorespiratory fitness as an effective, therapeutic intervention for metabolic syndrome and the prevention of progression to type 2 diabetes. A direct emphasis on physical activity and cardiorespiratory fitness certainly will have significant consequences on the prevalence of metabolic syndrome, obesity, progression to type 2 diabetes, and cardiovascular disease in the U.S. population.

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VII. FUTURE DIRECTIONS FOR RESEARCH It seems clear that regular exercise/physical activity has beneficial effects both for preventing and treating type 2 diabetes and metabolic syndrome. Particularly promising areas of research are: (a) the most effective amounts and intensities of exercise that lead to these benefits in individuals with diabetes; (b) investigating the unique role that resistance-training exercise may have on insulin sensitivity and metabolic syndrome; and (c) the interactions between exercise, environment, and genetics. We are currently in the early phases of a study of the separate and combined effects of aerobic and resistance exercise on individuals with aspects of the metabolic syndrome (central obesity, dyslipidemia, and sedentary lifestyle). We anticipate that such lines of investigation hold great promise for improving our effectiveness in diagnosing individuals with metabolic syndrome on the road to type 2 diabetes and in ultimately preventing its development in susceptible individuals.

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Nutrition and Diabetes: Pathophysiology and Management 13. Despres, J, Couillard, C, Gagnon, J, et al., Race, visceral adipose tissue, plasma lipids and lipoprotein lipase activity in men and women, the HERITAGE family study, Arter. Thromb. Vasc. Biol., 20:1932–38, 2000. 14. Wei, M, Gibbons, L, Mitchell, T, Kampert, J, Lee, C, and Blair, S, The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men, Ann. Intern. Med .,130:89–96, 1999. 15. Wei, M, Gibbons, L, Kampert, J, Nichaman, M, and Blair, S, Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes, Ann. Intern. Med., 132:605–11, 2000. 16. Blair, S, Kohl, HI, Paffenbarger, RJ, Clark, D, Cooper, K, and Gibbons, L, Physical Fitness and all-cause mortality. A prospective study of healthy men and women, JAMA, 262:2395–2401, 1989. 17. Blair, S, Kohl, HI, Barlow, C, Paffenbarger, RJ, Gibbons, L, and Macera, C, Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men, JAMA, 273:1093–98, 1995. 18. Fagard, R, Exercise characteristics and the blood pressure response to dynamic physical training, Med. Sci. Sports Exerc., 33:S484–492, 2001. 19. Blair, S, Kohl, HI, Barlow, C, and Gibbons, L, Physical fitness and all-cause mortality in hypertensive men, Ann. Med., 23:307–12, 1991. 20. Whaley, M, Kampert, J, Kohl, HI, and Blair, S, Physical fitness and clustering of risk factors associated with the metabolic syndrome, Med. Sci. Sports Exeric., 31:287–93, 1999. 21. Katzmarzyk, PT, Church, T, and Blair, S, Cardiorespiratory fitness attenuates the effects of metabolic syndrome on all-cause and cardiovascular disease mortality in men, Archives Intern. Med., 164:1092–97, 2004. 22. Kaplan, N, The Deadly Quartet: upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension, Archives Intern. Med., 149:1514–20, 1989. 23. Carroll, S, Cooke, C, and Butterly, R, Metabolic clustering, physical activity and fitness in nonsmoking, middle-aged men, Med. Sci. Sports Exerc., 32:2079–86, 2000. 24. Irwin, M, Ainsworth, B, Mayer-Davis, E, Addy, C, Pate, R, and Durstine, J, Physical activity and the metabolic syndrome in a tri-ethnic sample of women, Obes. Res., 10:1030–1037, 2002. 25. Lakka, T, Laaksonen, D, Lakka, H, et al., Sedentary lifestyle, poor cardiorespiratory fitness, and the metabolic syndrome, Med. Sci. Sports Exerc., 35:1279–1286, 2003. 26. Panagiotakos, D, Pitsavos, C, Chrysohoou, C, et al., Impact of lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study, Am. Heart J., 2004; 147:106–12, 2004. 27. Lee, C, Jackson, A, and Blair, S, US weight guidelines: is it also important to consider cardiorespiratory fitness? Internat. J. Obes. Relat. Metab. Disord., 22:2–7, 1998. 28. Wei, M, Kampert, J, Barlow, C, et al., Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men, JAMA, 282:1547–53, 1999. 29. Farrell, S, Braun, L, Barlow, C, Cheng, Y, and Blair, S, The relation of body mass index, cardiorespiratory fitness and all-cause mortality in women, Obes. Res., 2002; 10:417–23, 2002. 30. Lee, C, Blair, S, and Jackson, A, Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men, Am. J .Clin. Nutr., 69:373–80, 1999.

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31. Gagnon, J, Province, M, and Bouchard, C, The HERITAGE Family study: quality assurance and quality control, Ann. Epidemiol., 6:520–29, 1996. 32. Whelton, S, Chin, A, Xin, X, and He, J, Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials, Ann. Intern. Med., 136:493–503, 2002. 33. Halber, J, Silagy, C, Finucane, P, Withers, R, Hamdorf, P, and Andrews, G, The effectiveness of exercise training in lowering blood pressure: a meta-analysis of randomised controlled trials of 4 weeks or longer, J. Human Hypertens., 11:641–49, 1997. 34. Kelley, G and Sharpe, K, Aerobic exercise and resting blood pressure in older adults: a meta-analytic review of RCT's, J. Gerontol. Series A-Bio. Sci. Med. Sci. 56:298–303, 2001. 35. Kelley, G, Aerobic exercise and resting blood pressure among women: a metaanalysis, Prev. Med., 28:264–75, 1999. 36. Durstine, J and Haskell, W, Effects of exercise training on plasma lipids and lipoproteins, Exerc. Sport Sci. Rev., 22:477–524, 1994. 37. Leon, A and Sanchez, O, Response of blood lipids to exercise training alone or combined with dietary intervention, Med. Sci. Sports Exerc., 33:S502–515, 2001. 38. Kraus, W, Houmard, J, Duscha, B, et al., Effects of the amount and intensity of exercise on plasma lipoproteins, N. Engl. J. Med., 347:1483–92, 2002. 39. Boule, N, Haddad, E, Kenney, G, Wells, G, and Sigal, R, Effects of exercise on glycemic control and body mass in Type 2 Diabetes mellitus, JAMA, 286:1218–27, 2001. 40. Group UPDS, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837–53, 1998. 41. Group UPDS, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes, Lancet, 352:854–65, 1998. 42. Arciero, P, Vukovich, M, Holloszy, J, Racette, S, and Kohrt, W, Comparison of shortterm diet and exercise on insulin action in individuals with abnormal glucose tolerance, J. Appl. Physiol., 86:1930–35, 1999. 43. Walker, K, Piers, L, Putt, R, Jones, J, and O’Dea, K, Effects of regular walking on cardiovascular risk factors and body composition in normoglycemic women and women with Type 2 diabetes, Diabet. Care, 22:555–61, 1999. 44. Ross, R, Dagnone, D, Jones, P, et al., Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men: a randomized, controlled trial, Ann. Intern. Med., 133:92–103, 2000. 45. Ivy, J, Zderic, T, and Donovan, F, Prevention and treatment of non-insulin-dependent diabetes mellitus, Exerc. Sport Sci. Rev., 27:1–35, 1999. 46. Dowse, G, Zimmet, P, Gareeboo, H, et al., Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians, Diabet. Care, 14:271–82, 1991. 47. Pereira, M, Kriska, A, Joswiak, M, et al., Physical inactivity and glucose tolerance in the multiethnic island of Mauritius, Med. Sci. Sports Exerc., 27:1626–34, 1995. 48. Zimmet, P, Collins, V, Dowse, G, et al., The relation of physical activity to cardiovascular disease risk factors in Mauritians, Am. J. Epidemiol., 134:862–75, 1991. 49. Mayer-Davis, E, D’Agostino, R, Karter, A, Haffner, S, Rewers, M, Saad, M, Bergman, R, Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherolsclerosis Study, JAMA, 279:669–674, 1998.

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Nutrition and Diabetes: Pathophysiology and Management 50. Kriska, A, LaPorte, R, Pettitt, D, et al., The association of physical activity with obesity, fat distribution and glucose intolerance in Pima Indians, Diabetologia, 36:863–869, 1993. 51. Manson, J, Nathan, D, Krolewski, A, Stampfer, J, Willett, W, and Hennekens, C, A prospective study of exercise and incidence of diabetes among U.S. male physicians, JAMA, 268:63–67, 1992. 52. Manson, J, Rimm, E, Stampfer, J, et al., Physical activity and incidence of NIDDM in women, Lancet, 338:774–778, 1991. 53. Lipman, R, Raskin, P, Love, T, Triebwasser, J, Lecocq, F, and Schnure, J, Glucose intolerance during decreased physical activity in man, Diabetes, 21, 1972. 54. Lipman, R, Schnure, J, Bradley, E, and Lecocq, F, Impairment of peripheral glucose utilization in normal subjects by prolonged bed rest, J. Lab. Clin. Med., 76:221–30, 1970. 55. Misbin, R, Moffa, A, and Kappy, M, Insulin binding to monocytes in obese patients treated with carbohydrate restriction and changes in physical activity, J. Clin. Endocrinol. Metab., 56:273–78, 1983. 56. Stuart, C, Shamgraw, R, Prince, M, Peters, E, and Wolfe, R, Bed-rest-induced insulin resistance occurs primarily in muscle, Metabolism, 37:802–06, 1988. 57. Heath, G, Gavin, J, Hinderliter, J, Hagberg, J, Bloomfield, S, and Holloszy, J, Effects of exercise and lack of exercise on glucose tolerance and insulin sensitivity, J. Appl. Physiol., 55:512–17, 1983. 58. King, D, Dalsky, G, Clutter, W, et al., Effects of exercise and lack of exercise on insulin sensitivity and responsiveness, J. Appl. Physiol. 64:1942–46, 1988. 59. Mikines, K, Sonne, B, Tronier, B, and Galbo, H, Effects of training and detraining on insulin action in trained men, J. Appl. Physiol., 66:704–11, 1989. 60. Rogers, M, Yamamoto, C, King, D, Hagberg, J, Ehsani, A, and Holloszy, J, Improvement in glucose tolerance after 1 wk of exercise in patients with mild NIDDM, Diabet. Care, 11:613–18, 1988. 61. Seals, D, Hagberg, J, Allen, W, et al., Glucose tolerance in young and older athletes and sedentary men, J. Appl. Physiol., 56:1521–25, 1984. 62. Holloszy, J, Schultz, J, Kusnierkiewicz, J, Hagberg, J, and Eshani, A, Effects of exercise on glucose tolerance and insulin resistance: brief review and preliminary results, Acta. Med. Scand., 711:55–65, 1986. 63. Reitman, J, Vasquez, B, Klimes, I, and Nagulesparan, M, Improvement of glucose homeostasis after exercise training in NIDDM, Diabet. Care, 7:434–441, 1984. 64. Schneider, S, Amorosa, A, Khachadurian, A, and Ruderman, N, Studies on the mechanism of improved glucose control during regular exercise in type 2 (noninsulin-dependent) diabetes, Diabetologia, 26:355–360, 1984. 65. Dela, F, Larsen, J, Mikines, K, Ploug, T, Petersen, L, and Galbo, H, Insulin-stimulated muscle glucose clearance in patients with NIDDM: effects of one-legged physical training, Diabetes, 44:1010–20, 1995. 66. Group DPPR, Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346:393–403, 2002. 67. Braun, B, Zimmermann, B, and Kretchmer, N, Effects of exercise intensity on insulin sensitivity in women with NIDDM, J. Appl. Physiol., 78:300–306, 1995. 68. Hawley, J and Houmard, J, Introduction — Preventing insulin resistance through exercise: a cellular approach, Med. Sci. Sports Exerc., 36:1187–1190, 2004. 69. Berggren, J, Hulver, M, Dohm, G, and Houmard, J, Weight loss and exercise: implications for muscle lipid metabolism and insulin action, Med. Sci. Sports Exerc., 36:1191–95, 2004.

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70. Bruce, C and Hawley, J, Improvements in insulin resistance with aerobic exercise training: a lipocentric approach, Med Sci. Sports Exerc, 36:1196–1201, 2004. 71. Ivy, J, Muscle insulin resistance amended with exercise training: role of GLUT4 expression, Med. Sci. Sports Exerc., 36:1207–11, 2004. 72. Houmard, J, Tanner, C, Slentz, C, Duscha, B, McCartney, J, and Kraus, W, Effect of the volume and intensity of exercise training on insulin sensitivity, J. Appl. Physiol, 96:101–06, 2004. 73. Binder, E, Birge, S, and Kohrt, W, Effects of endurance exercise and hormone replacement therapy on serum lipids in older women, J. Am. Geriatr. Soc., 44:231–36, 1996. 74. Slentz, C, Duscha, B, Johnson, J, et al., Effects of the amount of exercise on body weight, body composition, and measures of central obesity, Arch. Intern. Med., 164:31–39, 2004. 75. Ekelund, L, Haskell, W, Johnson, J, et al., Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men: the Lipid Research Clinics Mortality Follow-up Study, N. Engl. J. Med., 319:1379–1384, 1988. 76. Meyers, J, Prakash, M, Froelicher, V, Do, D, Partington, S, and Atwood, J, Exercise capacity and mortality amount men referred for exercise testing, N. Engl. J. Med., 346:793–801, 2002. 77. Weiner, D, Ryan, T, Parsons, L, et al., Long-term prognostic value of exercise testing in men and women from the Coronary Artery Surgery Study (CASS) registry, Am. J. Card., 75:865–70, 1995. 78. Wei, M, Kampert, J, Barlow, C, et al., Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight and obese men, JAMA, 282:1547–53, 1999. 79. Slattery, M and Jacobs, DJ, Physical fitness and CVD mortality: the US Railroad Study, Am. J. Epidemiol., 127:571–80, 1988. 80. Peters, R, Cady, LJ, Bischoff, D, et al., Physical fitness and subsequent myocardial infarction in healthy workes, JAMA, 249:3052–56, 1993. 81. Wyns, W, Musschaert-Beauthier, E, van Domburg, R, et al., Prognostic value of symptom limited exercise testing in men with a high prevalence of coronary artery disease, Eur. Heart J., 6:939–45, 1985. 82. Roger, V, Jacobsen, S, and Pellikka, P, Prognostic value of treadmill exercise testing: a population-based study in Olmsted county, Minnesota, Circulation, 98:2836–41. 83. Gulati, M, Pandey, D, Arnsdorf, M, et al., Exercise capacity and the risk of death in women: The St. James Women Take Heart Project, Circulation, 108:1554–59, 2003. 84. Weinsier, R, Hunter, G, Heini, A, Goran, M, and Sell, S, The etiology of obesity: relative contribution of metabolic factors, diet & physical activity, Am. J. Med., 105:145–150, 1998. 85. Prentice, A, and Jebb S, Obesity in Britain: gluttony or sloth? Br. Med. J., 311:437–39, 1995. 86. Mayer, J, Marshall, N, Vitale, J, Christensen, J, Mashayekhi, M, and Stare, F, Exercise, food intake and body weight in normal rats and genetically obese adult mice, Am. J. Physiol., 177:544–48, 1954. 87. Mayer, J, Purnima, R, and Mitra, K, Relation between caloric intake, body weight, and physical work: studies in an industrial male population in West Bengal, Am. J. Clin. Nutr., 4:169–175, 1956.

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5

Metabolic Alterations in Muscle Associated with Obesity John P. Thyfault, Ph.D. and G. Lynis Dohm, Ph.D.

CONTENTS I. Introduction..................................................................................................79 II. Muscle Mitochondria and Uncoupling Protein in Obesity.........................80 III. Insulin Resistance in Obesity ......................................................................81 A. Blunted Muscle Insulin-Signal Transduction in Obesity ...................81 B. Activation of PKC May Cause Insulin Resistance ............................83 C. Relationship of Skeletal-Muscle Insulin Resistance and Intramyocellular Lipid Accumulation.................................................83 D. Inflammatory Pathways and Insulin Action in Obesity .....................85 E. Mechanisms Causing Insulin Resistance in Obesity..........................85 IV. Lipid Metabolism in Obesity ......................................................................85 A. Fatty-Acid Oxidation in Skeletal Muscle ...........................................86 B. Fatty-Acid Transport into Skeletal Muscle.........................................88 C. Metabolic Inflexibility Associated with Obesity ................................89 References................................................................................................................91

I. INTRODUCTION The obesity epidemic in developed countries brings into focus a need to understand the causes and the consequences of obesity. In this chapter we will review the role of muscle in the altered metabolism that is seen with obesity. The first part of the chapter will be a description of the differences in muscle carbohydrate, lipid, and energy metabolism between lean and obese individuals. In many cases, the changes in muscle metabolism that are observed in obese people can be directly linked to diseases, such as diabetes, that are increased by obesity. However, in cross-sectional studies that compare lean and obese subjects, one doesn’t know if the differences are caused by obesity or if they are themselves a cause for the individual to become obese. It is clear that there are genetic factors that predispose some people to become obese more easily than others. If we understood the metabolic differences that

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predispose people to become obese, we might be able to intervene with effective treatment. Thus, in a later section of the chapter, we present evidence for a hypothesis that disturbances in muscle-lipid metabolism may cause a person to be predisposed to become obese. We hope that the speculation presented will provide testable hypotheses that may lead to understanding the underlying mechanisms of obesity. Muscle is certainly an important organ to consider with regard to obesity, since it accounts for approximately 42 percent of the body mass87 and approximately 70 percent to 80 percent of the glucose of a meal goes to muscle. At rest, muscle accounts for about 25 percent of whole-body-oxygen consumption, while during a marathon, 90 percent of the energy expended goes to support muscular contraction. Thus, it is important to know the differences in muscle carbohydrate, lipid, and energy metabolism in obese individuals if we are to understand the causes and consequences of obesity.

II. MUSCLE MITOCHONDRIA AND UNCOUPLING PROTEIN IN OBESITY Energy contained in the food we eat is preserved in the chemical potential of adenosine triphosphate (ATP) after carbohydrates, lipids, and proteins are oxidized to carbon dioxide and water. Oxidation takes place inside mitochondria, and the energy of electron transfer through the electron-transport chain is maintained by extrusion of protons from the matrix, producing an electrochemical gradient across the inner mitochondrial membrane. Dissipation of the protein gradient through the F1 ATPase complex of the inner membrane then leads to ATP synthesis. It has long been known that brown adipose tissue has a high capacity for heat production, because the mitochondria of this tissue contains a protein called uncoupling protein (UCP1), which dissipates the proton gradient through the inner membrane, with the energy being released as heat instead of ATP synthesis. Since obesity is associated with energy imbalance, it was speculated that more uncoupling protein might protect against obesity. Evidence to support this hypothesis was provided by an experiment in which UCP1 was overexpressed in skeletal muscle. The UCP1 overexpressing transgenic mice were resistant to weight gain and obesity when placed on a high-fat diet.66 However, since UCP1 is normally only found in brown adipose tissue, and humans have little or no brown adipose tissue, the significance of UCP1 in human obesity is questionable. After the cloning of two proteins with high homology to UCP1 (UCP2 and UCP3), there was renewed interest in whether uncoupling proteins might be a factor in obesity. Both UCP2 and UCP3 were confirmed to cause uncoupling of oxidative phosphorylation. UCP2 is ubiquitously expressed, while UCP3 is primarily expressed, in muscle. UCP2 and UCP3 have been extensively studied, but there is no clear link between these uncoupling proteins and obesity.44 The physiological function of uncoupling proteins is somewhat puzzling. UCP3 expression is paradoxically increased by fasting and acute exercise, but these responses are secondary to the release of fatty acids, which are potent regulators of UCP3 transcription. Thus, there seems to be a link between lipid metabolism and

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the expression of UCP3 in muscle.95 Since altered lipid metabolism is related to insulin resistance (see later sections of this chapter), uncoupling proteins may play an indirect role in the changes in metabolism seen in obesity. In addition to producing ATP, mitochondria are also a major source of reactiveoxygen species, which can cause DNA damage and peroxidation of membrane lipids. Recent evidence suggests that one of the functions of uncoupling proteins in muscle may be to prevent the proton gradient across the inner mitochondrial membrane from becoming too high, which would lead to the production of harmful reactiveoxygen species.40,95 Damage to mitochondrial membranes and mitochondrial DNA by reactive-oxygen species may be responsible for the defects that have been observed in muscle mitochondria of diabetic and aged individuals.57,80 In fact, impaired mitochondrial activity may play a much larger role in disease than previously recognized, since insulin-resistant offspring of patients with type 2 diabetes were also recently found to have reduced capacity for oxidative phosphorylation.81

III. INSULIN RESISTANCE IN OBESITY The metabolic syndrome is a condition characterized by hyperinsulinemia, hypertension, visceral obesity, dyslipidemia, and glucose intolerance, which leads to increased risk of coronary-artery disease and type 2 diabetes. The National Health and Nutrition Examination Survey (NHANES III) indicated that 45 percent of the U.S. population over age 50 has metabolic syndrome, and, because of the increase in the prevalence of obesity, the incidence of the metabolic syndrome has increased by 60 percent over the last decade. Obesity is generally accompanied by insulin resistance, which is manifest as fasting hyperinsulinemia. In addition, an elevated area under the curve for insulin values during an oral glucose-tolerance test is usual for insulin-resistant, obese individuals, and glucose utilization is markedly depressed in euglycemic insulinclamp studies.58,59 Stimulation of glucose transport by insulin is markedly blunted in muscle of obese individuals.27,34,59,82 This observation likely explains the decreased in vivo glucose disposal observed in insulin-resistant individuals, because muscle is the primary tissue for glucose disposal, and glucose transport into muscle is the ratelimiting step for glucose utilization.33, 35, 86, 88

A. BLUNTED MUSCLE INSULIN-SIGNAL TRANSDUCTION

IN

OBESITY

The inability of insulin to stimulate glucose transport in muscle of obese individuals raises the question as to whether this effect is caused by a defect in the glucosetransport system (i.e., glucose transporter 4 [GLUT4] translocation and activation) or in the insulin signaling system (i.e., insulin-signal transduction). To differentiate between these alternative mechanisms for insulin resistance, a number of experiments have been conducted to test whether glucose transport could be stimulated in insulin-resistant muscle if a signal other than insulin were presented. Exercise and muscle contraction have been shown to stimulate glucose transport by causing translocation of glucose transporters to the cell surface, analogous to the stimulation by insulin.36 Maximal stimulation of transport by insulin and exercise are additive,

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suggesting that the two stimuli act through different signaling pathways. Several groups have investigated stimulation of glucose transport in the insulin-resistant muscle of obese rats and have observed normal stimulation by muscle contraction, even though insulin stimulation was severely impaired.16,28 Kennedy et al.60 confirmed this finding in human subjects. This suggests that the glucose-transport system, (i.e., translocation and activation of glucose transporters) can respond if an alternative signal is transmitted. In our in vitro human-muscle preparations we have not been able to study muscle contraction, but stimulation of transport by hypoxia occurs by the same signaling pathway as contraction; stimulation by insulin and hypoxia are additive, but stimulation by contraction and hypoxia are not additive.20 The finding that stimulation of transport by hypoxia was normal in muscle of obese patients seems to confirm that the glucosetransport system is intact in insulin-resistant muscle.7 Likewise, we have observed that stimulation of transport by alkaline conditions was normal in muscle of obese patients,19 suggesting that several stimuli can stimulate transport in insulin-resistant muscles. Another line of evidence that a defect in insulin signaling causes insulin resistance comes from our experiments with serine/threonine and tyrosine protein phosphatase inhibitors. These experiments were based on the fact that insulin initiates a cascade of tyrosine and serine/threonine kinase activations. Therefore, inhibiting the opposing phosphatases mimics insulin action, but without the need for the defective step in the signaling pathway. The serine/threonine phosphatase inhibitor, okadaic acid, and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate all produced robust stimulation of glucose transport in insulin-resistant muscle of obese patients.19 A more direct set of observations that demonstrate a defect in the insulinsignaling pathway of insulin-resistant muscle come from studies in which the early steps in the signaling pathway were measured in normal and insulin-resistant muscle. Goodyear et al.38 found that autophosphorylation of the insulin receptor, phosphorylation of IRS-I, and activation of PI 3-kinase were all depressed in incubated human muscle from obese, insulin-resistant patients. Brozinick et al.17 demonstrated that protein kinase B (PKB/Akt) activation is also depressed in insulin-resistant muscle of obese individuals. Further evidence that the proximal steps in insulin signaling are depressed in obesity is demonstrated by the experiments of Leng et al.65 They found that in muscle of lean animals both insulin and muscle contraction activate the enzymes of the MAP kinase pathway (c-Jun NH2-terminal kinase [JNK], p38 MAPK, and extracellular signalrelated kinase [ERK 1 and 2]). Insulin stimulation of the MAPK enzymes was blunted in obese muscle, but contraction caused a normal response. This seems to suggest that the distal-signaling proteins respond normally if stimulated, and the depressed-insulin response in obese muscle was due to defects in the proximal steps. The insulin receptor tyrosine-kinase activity is depressed in muscle of obese individuals.4,53,76,77 In Pima Indians, insulin receptor autophosphorylation correlated well with glucose disposal,109 and the correlations were also found in cultured myoblasts.110 The mechanism that decreases insulin receptor tyrosine kinase activity has been investigated. We observed that removing phosphates from the receptors of obese individuals with alkaline phosphatase restored tyrosine-kinase activity,53,112 suggesting that phosphorylation of insulin receptors on serine or threonine residues

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83

might be the cause of inactivation. Hyperphosphorylation and inactivation of the insulin receptor has also been observed in insulin-resistant muscle of patients with polycystic-ovary syndrome30 and gestational diabetes. 97 Serine/threonine phosphorylation of IRS-1 may also be a potential mechanism for the inactivation of insulin-signal transduction.111Infusing rats with fatty acids for 3–4 hours caused decreased insulin receptor and IRS-1 tyrosine phosphorylation in response to insulin. IRS-1 was phosphorylated on serine 307 which makes it a less favorable substrate for the insulin receptor kinase.48

B. ACTIVATION

OF

PKC MAY CAUSE INSULIN RESISTANCE

Protein kinase C (PKC) can directly phosphorylate and inactivate the insulin receptor.67 Likewise, overexpression of PKC isoforms in cultured cells causes phosphorylation of the insulin receptor and insulin resistance.14,22 These findings led to the hypothesis that PKC causes insulin resistance in skeletal muscle.23 Several groups have reported that PKC activity and protein were increased in muscle of animals with insulin resistance.6,29,45,64,93,94 To determine if one of the PKC isoforms is increased in insulinresistant muscle and causes serine/threonine phosphorylation of the insulin receptor, we measured the protein content of eight PKC isoforms in the membrane fractions of muscles from lean and obese patients. The only PKC isoform that was increased in the membrane of insulin-resistant muscle (obese) was PKCβ. Basal PKCβ was higher in the in vitro incubated muscle of obese individuals, and insulin increased PKCβ in the membrane fraction in muscle of obese, but not lean, patients.53 To demonstrate a cause-and-effect relationship between PKC activity and insulin action, we incubated human-muscle strips in the presence and absence of PKC activators and inhibitors. In insulin-resistant muscle, the PKC inhibitor GF109203X enhanced insulin stimulation of glucose transport. In insulin-sensitive muscle, incubation with the PKC activator dPPA caused insulin-stimulated glucose transport to be depressed.25 These data suggest that a PKC activator can cause insulin resistance and that a PKC inhibitor can reverse insulin resistance. Other research groups have made observations that also implicate PKC in the development of lipid-induced insulin resistance. Griffen et al.,41 using a rat model, induced insulin resistance with a 5 h lipid/heparin infusion and observed a 50 percent reduction in insulin-stimulated IRS-1-associated PI-3 kinase activity, blunted IRS1 tyrosine phosphorylation, and a fourfold increase in PKC activity. In humans, Itani et al.52 also employed a lipid/heparin infusion and reported that insulin-stimulated glucose disposal was reduced by 43 percent, and skeletal-muscle diacylglycerol mass and PKC activity were increased fourfold. These findings not only imply that PKC activation causes skeletal-muscle insulin resistance, but also demonstrate an association between lipid accumulation (diacylglycerols) and PKC activation.

C. RELATIONSHIP OF SKELETAL-MUSCLE INSULIN RESISTANCE INTRAMYOCELLULAR LIPID ACCUMULATION

AND

It is well-established that intramyocellular triacylglycerol (IMTG) accumulation is associated with skeletal-muscle insulin resistance.10,56,73 However, it is unlikely that

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triacylglycerols are the culprit for reduced skeletal-muscle insulin action, but more likely they are an inert marker of other lipid intermediates known to suppress insulin sensitivity. An increase in the intramyocellular concentration of lipid intermediates such as fatty acyl-CoAs,50 ceramides,3,39 and diacylglycerols52 not only correlate with insulin resistance but also directly and indirectly alter insulin signaling.92 Considerable evidence linking increased skeletal-muscle lipid content to insulin resistance has been derived from animal studies employing acute and chronic high-fat diets.24 Fatty acid-induced insulin resistance appears to occur in concert with increased fatty acyl-CoAs.24 Moreover, insulin sensitivity is restored by treatments that reduce intramyocellular lipid accumulation (i.e., low-fat feeding and fasting).78 Similar findings have been observed in humans. Bachmann et al.8 reported significant increases in intramyocellular lipid content and reductions in insulin sensitivity following intravenous-lipid infusion. Ellis et al.31 demonstrated a negative correlation between insulin-mediated glucose disposal and fatty acyl-CoA content in skeletal muscle from a group of older men. Our laboratory observed blunted insulin-mediated glucose disposal in skeletal muscle from moderately and morbidly obese patients that was accompanied by elevated levels of intramyocellular fatty acyl-CoAs.50 After weight loss, insulin sensitivity was restored, and fatty acyl-CoA levels were also normalized.49 Thus, fatty acyl-CoAs, or a derived lipid, are related to, and possibly responsible for, muscle-insulin resistance. Various intramyocellular lipid intermediates, such as fatty acyl-CoAs, ceramides, and diacylglycerols, inhibit specific steps in the insulin-signaling cascade.92 Ceramides activate a protein phosphatase that dephosphorylates Akt/PKB, resulting in inhibition of GLUT4 translocation and glycogen synthesis21, 68. Diacylglycerols have been implicated in the activation of PKC in various tissues.24,92,99 Fatty acyl-CoAs have been shown to directly activate PKC in brain tissue15, 98, but these observations have yet to be observed in skeletal muscle. In models of high-fat exposure, intramyocellular fatty acylCoAs are elevated in concert with increased PKC activation.52 Moreover, fatty acylCoAs are also implicated in the indirect activation of PKC, as they are precursors for diacylglycerols formation. Diacylglycerol levels are elevated in many models of insulin resistance92, and these intermediates directly activate PKC,63,75 One of the difficulties with the lipotoxicity hypothesis of insulin resistance is the apparent paradox of increased IMTG in muscle of highly trained athletes, who are very insulin sensitive.37 However, the recent report by He, et al.43 may help to understand the role of muscle lipids in insulin resistance. They measured the size and quantity of mitochondria and lipid droplets in muscle from obese patients before and after weight loss and an endurance-exercise trial. After weight loss and exercise, the subjects improved insulin sensitivity by approximately 40 percent, but there was no change in the amount of intramuscular lipid. However, the mitochondria were larger, the lipid droplets were smaller, and the change in size of both mitochondria and lipid droplets correlated with the improvement in insulin sensitivity. They speculate that the smaller lipid droplets have a larger surface area that provides access for hydrolysis and utilization. In addition, the ratio of mitochondria to lipid droplets would also be important in the improved utilization of fat, which was characteristic of the subjects after weight loss and exercise.

Metabolic Alterations in Muscle Associated with Obesity

D. INFLAMMATORY PATHWAYS

AND INSULIN

ACTION

IN

85

OBESITY

The proinflammatory cytokine tumor necrosis factor alpha (TNFα) has also been proposed as a link between adiposity and the development of insulin resistance.47 TNFα initiates an inflammatory response by stimulating IκB kinase-β (IκK-β). Serine phosphorylation of inhibitor protein of κB (IκB) triggers ubiquitination and degradation of IκB, and, eventually, activation of the nuclear factor κB (NF-κB), a transcription factor involved in immune and inflammatory responses. TNFα is highly expressed in adipose tissue, and infusion of TNFα into rats caused insulin resistance, while neutralization of the cytokine with antibodies to TNFα reversed insulin resistance in obese rats. The insulin resistance induced by TNFα can be prevented by treatment with the salicylate, which is known to inhibit IκKβ. Treatment of adipocytes and skeletal muscle with TNFα causes insulin resistance by decreasing insulin-induced IRS-1 tyrosine phoshorylation and activation of IRS-1-associated PI 3-kinase. This is likely caused by phosphorylation of serine 307 of the IRS-1 protein. The serine kinase that is directly responsible for the phosphorylation of IRS-1 has not been determined with certainty, but candidates include c-Jun N-terminal kinase (JNK),47 PKC,61 and IκKβ.26 The insulin resistance induced by muscle lipids may also be mediated through inflammatory pathways.79 Kim et al.61 found that infusion of fatty acids into rats caused insulin resistance and decreased insulin signaling in skeletal muscle. Lipidinduced insulin resistance could be prevented by pretreating the rats with salicylate, a known inhibitor of IκK-β. Likewise, fatty-acid infusion in an IκKβ knock-out mouse did not produce insulin resistance as it did in wild-type controls.

E. MECHANISMS CAUSING INSULIN RESISTANCE

IN

OBESITY

Although the mechanisms that cause insulin resistance in muscle are not known with certainty, there appear to be some generally accepted concepts that form the basis of a model that serves as the basis for future hypothesis testing. In response to either TNFα or intramuscular lipids (fatty acyl-CoA, diacylglycerol, or ceramides), there is activation of a serine kinase (PKC, JNK, or IκKβ) and inactivation of a protein phosphatase (PP2A), such that IRS-1 and the insulin receptor become serine phosphorylated. These events then depress insulin-signal transduction to cause insulin resistance. Figure 5.1 displays a representation of insulin signaling in a muscle cell.

IV. LIPID METABOLISM IN OBESITY Obesity is associated with an increased storage of triglycerides in skeletal muscle (IMTG), accumulation of lipid intermediates (long-chain fatty acyl-CoAs, diacylglycerols, and ceramides) and subsequent insulin resistance. The question then presents itself: Why is there an accumulation of muscle lipids in obesity?

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Insulin Receptor

TNFα Receptor Ikk β

IRS-1/2 tyrosine Phos IRS-1/2 serine Phos

JNK

+

– PKC (θ or βll)

PI 3 Kinase IMTG GLUT4

Fatty Acyl-CoA

DAG

FIGURE 5.1 Proposed mechanism(s) for insulin resistance in skeletal muscle. DAG, diacylglycerols: IMTG, intramyocellular triacylglycerols; PKC, protein kinase C; JNK, c-Jun N terminal kinase; IKK, IkB kinase-; IRS-1/2, insulin receptor substrate 1 and 2; P13K, phosphatidylinositol 3-kinase; GLUT4, glucose transporter 4; (+), activation; (–), inhibition.

A. FATTY-ACID OXIDATION

IN

SKELETAL MUSCLE

When fatty acids are transported into skeletal muscle they are partitioned into one of two pathways: synthesis, resulting in formation of IMTG, or oxidation, resulting in energy production. Under normal conditions, most fatty acids are shunted towards oxidation, but evidence demonstrates this is not always the case in obesity. A reduced ability to oxidize free fatty acids is a probable explanation for an accumulation of IMTGs and lipid intermediates found in the skeletal muscle of obese individuals. Obesity is also associated with a large surplus of fat, both in storage, adipose tissue, and in circulation (plasma free fatty acids). Therefore, decreased fat oxidation in skeletal muscle likely plays a role in dislipidemia and obesity. Several studies have examined the impact of obesity on lipid metabolism at the whole-body level. Some studies show no difference or an increase in fat oxidation in obese compared to nonobese subjects,46,54,104,107 however, other studies have demonstrated that rates of whole-body fat utilization are lower in obese than nonobese subjects.85,113 Because these measures were obtained at the whole-body level, it is difficult to ascertain the effect of other tissues, including liver and adipose, on these results. Kelley et al.55 examined fatty-acid uptake and indirect calorimetry across the leg in a large sample of obese and nonobese subjects. This model allowed for a measure of metabolism across the muscle of the leg without a large degree of interference from other tissues. Respiratory quotient (RQ, obtained from arterio-venous samples) was significantly higher in obese than nonobese subjects, indicating reduced fattyacid utilization with obesity. Basal RQ values also correlated indirectly with the insulin sensitivity of the subjects, demonstrating that fat utilization could play a role in IMTG accumulation and insulin resistance. Fat oxidation in skeletal muscle involves several enzymes, but one of key importance is carnitine palmitoyltransferase 1 (CPT-1). Upon entry of the muscle cell, long-chain fatty acids are first converted to fatty acyl-CoAs in the cytosol and then transported across the outer mitochondrial membrane by the enzyme CPT-1. The

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activity or ability of CPT-1 to transport fatty acyl-CoAs into the mitochondria is believed to be the rate-limiting step of fat oxidation in skeletal muscle.89 Malonyl coenzyme A (malonyl CoA), the product of acetyl coenzyme A carboxylase (ACC), allostericaly binds to and inhibits CPT-1 activity,74 thereby inhibiting transport of fatty acyl-CoAs into the mitochondria. The importance of the malonyl CoA–CPT1 interaction upon rates of fat oxidation has been demonstrated in response to many stimuli.84,89,90 Transgenic mice that lack the ACC enzyme (no production of malonyl CoA) have increased rates of fat oxidation and reduced rates of fat storage1. In addition, the same ACC knockout mice are resistant to weight gain and maintain normal insulin sensitivity in response to a high-fat diet.1 An in vivo human study demonstrated that hyperglycemia/hyperinsulinemia decreases long-chain fatty acid oxidation through increasing muscle malonyl-CoA content, but had no effect upon oxidation of medium-chain fatty acids that enter the mitochondria independently of CPT-1.83 The regulation of CPT-1 by malonyl CoA is thus an important regulator of fatty-acid oxidation and also plays a role in metabolic flexibility, which is discussed later. Additional studies have examined this and other enzymes that are important for skeletal-muscle fat oxidation in obesity. Initial work from our laboratory examined fatty-acid oxidation at the in vitro level in muscle from obese and nonobese subjects. Using a whole homogenate preparation from vastus-lateralis biopsies, we found that obese muscle has a reduced rate of lipid oxidation, as well as reduced CPT-1 and citrate synthase activity.62 In addition, CPT-1 and citrate synthase activities were both inversely correlated with levels of adiposity. Studies from other groups have found similar results, mainly that citrate synthase activity and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity are depressed in muscle from obese/insulin-resistant subjects.100,101,113 In relation to this, muscle from obese/insulin-resistant subjects has been shown to have increased activities of glycolytic enzymes. Simoneau et al. 101 found that the ratio between glycolytic and oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity. These data led us to hypothesize that skeletal muscle from obese subjects possessed a decrement in fatty-acid oxidation, leading to lipids being shunted to the synthetic pathway, resulting in an accumulation of IMTGs and subsequent insulin resistance. Our lab has also examined lipid metabolism in intact muscle strips (rectus abdominus) obtained from nonobese, moderately overweight, and extremely obese subjects.50 Incubating intact muscle strips allowed for the tracking of labeled palmitate into synthesis or oxidation. As expected, muscle from extremely obese subjects displayed a decrement in lipid oxidation (58 percent) when compared to muscle from nonobese. The lipids entering extremely obese muscle were preferentially partitioned toward triglyceride synthesis at a rate twofold higher than that found in nonobese muscle (calculated from a ratio of oxidation/storage). However, muscle from moderately overweight individuals had rates of lipid oxidation and synthesis that were equal to that from nonobese muscle. Interestingly, muscle from moderately overweight individuals had the same increased levels of lipid metabolite content (long-chain fatty acyl-CoA) and the same levels of insulin resistance that is observed in muscle from the extremely obese. Therefore, depressed rates of lipid oxidation

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could not be the only mechanism causing IMTG accumulation in skeletal muscle from obese subjects.

B. FATTY-ACID TRANSPORT

INTO

SKELETAL MUSCLE

When examining substrate usage by cellular systems it is important that there be a match between rates of substrate uptake and rates of substrate metabolism. Therefore, an increased rate of fatty-acid uptake may be a potential mechanism responsible for IMTG accumulation in obese skeletal muscle. We and others have reported that obesity is associated with hyperlipidemia.71 As a result, fatty-acid uptake may be increased in obese skeletal muscle due to oversupply and increased rates of fattyacid uptake. It was once thought that fatty acids entered the muscle cell solely through passive diffusion. It is now apparent that fatty acids can also enter through a protein-mediated mechanism.2,11,12 The proteins involved in the process include: fatty-acid-binding protein-plasma membrane (FABPpm), which is associated with the plasma membrane,102 and fatty-acid translocase (FAT/CD36), which is found both at the sarcolemma and in intracellular pools.2 In addition, a third protein, fatty-acid transporter protein 1 (FATP1), is thought to be involved in the process, but it is less understood and may act as an acyl-CoA synthase.2,91 Transport of fatty acids into the cell is a dynamic process upregulated by both contraction and insulin stimulation. Contraction and insulin both activate the translocation of FAT/CD36 from intracellular stores to the plasma membrane.11,70 During the same conditions, rates of fatty-acid uptake are elevated, demonstrating that FAT/CD36 is the primary protein involved in facilitated transport. Stimulation of fatty-acid transport by insulin and muscle contraction occur through different mechanisms and are additive.11 Therefore, there are two mechanisms regulating fatty-acid transport in muscle: acute regulation through translocation of FAT/CD36 (following insulin and contraction) and chronic regulation through increased expression of transporter proteins.11 There is ample evidence suggesting that muscle fatty-acid transport is altered with insulin resistance. Studies examining aging and insulin resistance have shown that skeletal muscle from older animals has increased rates of palmitate uptake in response to insulin compared to young animals.105 Obese, insulin-resistant Zucker rats have also been shown to have elevated rates of fatty-acid transport.106 Although expression of transporter proteins was not elevated in obese Zucker rats, sarcolemmal concentrations of FAT/CD36 are elevated, and translocation of FAT/CD36 back to intracellular stores is seemingly impaired. A recent study from Bonen et al.13 examined fatty-acid transport in skeletal muscle from human subjects who were obese, type 2 diabetic, and healthy controls. They showed that fatty-acid transport was fourfold higher in obese and type 2 diabetic skeletal muscle, which was associated with increased IMTG content. They also found that increased fatty-acid transport was not associated with an increased expression of FAT/CD36 or FABPpm. However, they did find that sarcolemmal content of FAT/CD36, but not FABPpm, were higher in the muscle of obese and type 2 diabetic patients compared to controls. So, as with the muscle from obese Zucker rats, human obesity and type 2 diabetes is

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associated with increased FAT/CD36 at the sarcolemma, which forces rapid entry of fatty acids into muscle. This provides an interesting complexity in insulin-resistant muscle where GLUT4 (glucose transporters) are unable to readily translocate from intracellular pools to the sarcolemma, and FAT/CD36 (fatty-acid transporters) are unable to leave the sarcolemma and return to intracellular pools. As suggested by Bonen et al.,13 this results in a juxtaposed relationship between glucose and fattyacid transporters, creating an environment for insulin resistance and increased stores of IMTGs and other lipid metabolites. We can only speculate on the series of events that leads to insulin resistance in skeletal muscle. However, it is certain that increased levels of IMTG and concurrent lipid metabolites trigger skeletal-muscle insulin resistance. Why lipids accumulate in skeletal muscle of obese/insulin-resistant individuals is not completely understood. However, there is ample evidence demonstrating that increased rates of fattyacid uptake alone or in combination with decreased rates of fatty-acid oxidation play a significant role.

C. METABOLIC INFLEXIBILITY ASSOCIATED

WITH

OBESITY

Healthy skeletal muscle adapts to differing concentrations of plasma substrates (carbohydrates and fats) and hormones (primarily insulin). When a substrate is in oversupply, healthy skeletal muscle is able to adjust and activate processes that are necessary for appropriate oxidation or storage. Accordingly, healthy muscle is also able to adjust substrate utilization in response to hormonal changes. This process has been termed metabolic flexibility and constantly occurs in daily life when conditions move from fasting to fed to fasting again. This term was coined by Kelley and colleagues55 following a study (previously mentioned) in which they measured differences in substrate utilization during basal- and insulin-stimulated conditions across the leg in obese and nonobese subjects. During fasting conditions, obese individuals had significantly higher rates of carbohydrate oxidation and decreased fat oxidation, which fit the hypothesis for reduced oxidative capacity in obese skeletal muscle. When moving from basal to euglycemic/hyperinsulinemic conditions, the nonobese subjects increased rates of carbohydrate oxidation and decreased fat oxidation, indicating an appropriate response to an increase of plasma glucose and insulin. This adaptation or flexibility did not occur in obese individuals. Figure 5.2 demonstrates rates of fat and carbohydrate oxidation as measured in the study by

basal

insulin

Fat Oxidation

basal

insulin

Carbohydrate Oxidation

FIGURE 5.2 Metabolic flexibility in Δ Obese and  Lean-NonObese subjects during basal and insulin-stimulated conditions. Data derived from Kelley et al., Am. J. Physiol., 277, 1999.

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Kelley et al.55 Therefore, the obese subjects displayed metabolic inflexibility, as their skeletal muscle was unable to adapt to changes in their nutritional environment. Measures of muscle metabolism from our laboratory and others may provide insight into the metabolic inflexibility found with obesity. Lean skeletal muscle has higher basal- and insulin-stimulated glucose uptake than muscle from obese, and this could affect the ability of obese individuals to increase carbohydrate reliance during postabsorptive conditions. Preliminary data from our laboratory suggests another possible mechanism51. We have measured rates of fatty-acid uptake under basal- and insulin-stimulated conditions in skeletal muscle from lean and obese. Uptake values in obese muscle were twofold and threefold greater under basal- and insulin-stimulated conditions, respectively, compared to nonobese. Fatty-acid uptake was increased (twofold) in response to insulin in obese muscle, while this did not occur in lean muscle. This is interesting, as obesity is associated with an opposite response of insulin upon glucose uptake. Therefore, it is possible that altered rates of glucose and fatty-acid uptake affect cellular substrate availability and influence substrate reliance directly or through signaling events. A clear association can be linked between metabolic inflexibility and a defect in lipid oxidation measured with obesity. In normal conditions, an increase in dietary fat or plasma lipids is met with adaptations that increase lipid metabolism in skeletal muscle. In rodent studies, in which plasma fatty-acids levels are significantly increased (fasting, high-fat feedings, streptozotocin-induced diabetes) there is an equivalent increase in the expression and activity of lipid-metabolizing enzymes in skeletal muscle, including malonyl-CoA decarboxylase, CPT-1, β-HAD, pyruvate dehydrogenase kinase 4, and FAT/CD36.72,108 In healthy, nonobese humans, five days of a high-fat diet increased lipid oxidation (measured by RQ) during submaximal exercise and increased genes important for fat oxidation, including FAT/CD36, FABPpm, β-HAD, and CPT-1.18 In another study, nonobese subjects increased total daily fat oxidation (measured in indirect calorimetry chamber) after seven days of a high-fat diet.96 These data demonstrate that nonobese individuals can increase lipid oxidation when needed. Conversely, it appears that obese individuals lack an ability to increase lipid oxidation following dietary manipulation. Astrup et al.5 compared lipid oxidation between previously obese and lean women following three days of a high fat-diet (50 percent fat). Lean women adjusted rates of fat oxidation to the diet. However, previously obese (post weight loss) women could not increase fat oxidation, resulting in positive fat balance and storage. As previously mentioned, the CPT-1–malonyl-CoA interaction in skeletal muscle probably plays a role in metabolic flexibility. Plasma insulin and glucose dictate malonyl-CoA content in muscle. Therefore, the altered substrate utilization associated with obesity could be related to a dysregulation of muscle malonyl-CoA content. Preceding enzymatic dysregulation, the response of gene expression to changes in the nutritional environment may be malfunctioning in skeletal muscle of obese subjects. Peroxisome proliferators-activated receptors (PPARs) are the first genetic sensors known to respond to changes in lipids.32 PPARs are activated by changes in dietary fat and metabolic derivatives, and then enact their response by changing the expression of proteins regulating fat metabolism. The PPAR-α receptor has been shown to enhance skeletal-muscle lipid oxidation. Therefore, a defect in the PPAR-α

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response to lipids is a possible candidate for the reductions in lipid oxidation and the lack of metabolic flexibility in skeletal muscle from obese subjects. In conclusion, our in vitro skeletal-muscle studies show that obese skeletal muscle possesses defective rates of lipid oxidation. This leads to another question: Is defective lipid oxidation the “chicken” or the “egg” of obesity? Do preobese individuals possess muscle that is defective in metabolizing fat, or does this occur after the onset of obesity? We believe that defective lipid oxidation in skeletal muscle plays a likely role in the onset of obesity based on the following factors: 1) genetic work involving families and twins demonstrates that genetic factors at least predispose individuals to obesity,69 and that part of these genetic factors are related to energy expenditure, and, assumedly, defective lipid metabolism; 2) a short-term, prospective study in Pima Indians demonstrated that elevated RQ values were correlated with increased weight gain over four years103; 3) a study from our lab has shown that women who were previously extremely obese but had lost approximately 100 lbs (gastric-bypass surgery) had significantly lower rates of fat utilization during exercise compared with healthy women matched for BMI42; 4) recently, we have performed primary-cell cultures of muscle from lean and obese individuals, and we see the same defect in rates of lipid oxidation in cultured obese muscle that are measured in vitro,9 demonstrating a distinct phenotype that is unaltered when removing muscle from its environment; and 5) finally, in transgenic animal models where rates of lipid oxidation are elevated, animals are resistant to high-fat diets and do not gain weight, demonstrating that an increased metabolic capacity can withstand overfeeding.1 These studies provide evidence that a disturbance in muscle-lipid metabolism may lead to obesity. Currently, scientists are examining the effect of exercise and pharmacological treatments upon lipid metabolism in skeletal muscle. These studies will provide insight into the prevention of obesity and its related comorbidities.

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54. Kanaley, JA, MM Weatherup-Dentes, CR Alvarado, and G Whitehead, Substrate oxidation during acute exercise and with exercise training in lean and obese women, Eur. J. Appl. Physiol., 85:68–73, 2001. 55. Kelley, DE, B Goodpaster, RR Wing, and JA Simoneau, Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss, Am. J. Physiol., 277:E1130–1141, 1999. 56. Kelley, DE and BH Goodpaster, Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance, Diabet. Care, 24:933–941, 2001. 57. Kelley, DE, J He, EV Menshikova, and VB Ritov, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes, 51:2944–2950, 2002. 58. Kelley, DE and LJ Mandarino, Fuel selection in human skeletal muscle in insulin resistance: a reexamination, Diabetes, 49:677–683, 2000. 59. Kelley, DE, MA Mintun, SC Watkins, JA Simoneau, F Jadali, A Fredrickson, J Beattie, and R Theriault, The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle, J. Clin. Invest., 97:2705–2713, 1996. 60. Kennedy, JW, MF Hirshman, EV Gervino, JV Ocel, RA Forse, SJ Hoenig, D Aronson, LJ Goodyear, and ES Horton, Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes, Diabetes, 48:1192–1197, 1999. 61. Kim, JK, YJ Kim, JJ Fillmore, Y Chen, I Moore, J Lee, M Yuan, ZW Li, M Karin, P Perret, SE Shoelson, and GI Shulman, Prevention of fat-induced insulin resistance by salicylate, J. Clin. Invest., 108:437–446, 2001. 62. Kim, JY, RC Hickner, RL Cortright, GL Dohm, and JA Houmard, Lipid oxidation is reduced in obese human skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 279:E1039–1044, 2000. 63. Kishimoto, A, Y Takai, T Mori, U Kikkawa, and Y Nishizuka, Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover, J. Biol. Chem., 255:2273–2276, 1980. 64. Koya, D and GL King, Protein kinase C activation and the development of diabetic complications, Diabetes, 47:859–866, 1998. 65. Leng, Y, TL Steiler, and JR Zierath, Effects of insulin, contraction, and phorbol esters on mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice, Diabetes, 53:1436–1444, 2004. 66. Li, B, LA Nolte, JS Ju, DH Han, T Coleman, JO Holloszy, and CF Semenkovich, Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice, Nat. Med., 6:1115–1120, 2000. 67. Liu, F and RA Roth, Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites, FEBS Lett., 352:389–392, 1994. 68. Long, SD and PH Pekala, Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes, Biochem. J., 319 (Part 1):179–184, 1996. 69. Loos, RJ and C Bouchard, Obesity — is it a genetic disorder? J. Intern. Med., 254:401–425, 2003. 70. Luiken, JJ, DJ Dyck, XX Han, NN Tandon, Y Arumugam, JF Glatz, and A Bonen, Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane, Am. J. Physiol. Endocrinol. Metab., 282:E491–495, 2002.

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Nutrition and Diabetes: Pathophysiology and Management 71. MacLean, PS, S Vadlamudi, KG MacDonald, WJ Pories, JA Houmard, and HA Barakat, Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women, Metabolism, 49:285–292, 2000. 72. McAinch, AJ, JS Lee, CR Bruce, RJ Tunstall, JA Hawley, and D Cameron-Smith, Dietary regulation of fat oxidative gene expression in different skeletal muscle fiber types, Obes. Res., 11:1471–1479, 2003. 73. McGarry, JD, Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes, Diabetes, 51:7–18, 2002. 74. McGarry, JD, SE Mills, CS Long, and DW Foster, Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat, Biochem. J., 214:21–28, 1983. 75. Nishizuka, Y, Turnover of inositol phospholipids and signal transduction, Science, 225:1365–1370, 1984. 76. Nolan, JJ, G Freidenberg, R Henry, D Reichart, and JM Olefsky, Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulindependent diabetes mellitus and obesity, J. Clin. Endocrinol. Metab., 78:471–477, 1994. 77. Nyomba, BL, VM Ossowski, C Bogardus, and DM Mott, Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans, Am. J. Physiol., 258:E964–974, 1990. 78. Oakes, ND, KS Bell, SM Furler, S Camilleri, AK Saha, NB Ruderman, DJ Chisholm, and EW Kraegen, Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA, Diabetes, 46:2022–2028, 1997. 79. Perseghin, G, Cellular mechanisms of insulin resistance by salicylate, Int. J. Obes., 27:S6–S11, 2003. 80. Petersen, KF, D Befroy, S Dufour, J Dziura, C Ariyan, DL Rothman, L DiPietro, GW Cline, and GI Shulman, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science, 300:1140–1142, 2003. 81. Petersen, KF, S Dufour, D Befroy, R Garcia, and GI Shulman, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes, N. Engl. J. Med., 350:664–671, 2004. 82. Petersen, KF, R Hendler, T Price, G Perseghin, DL Rothman, N Held, JM Amatruda, and GI Shulman, 13C/31P NMR studies on the mechanism of insulin resistance in obesity, Diabetes, 47:381–386, 1998. 83. Rasmussen, BB, UC Holmback, E Volpi, B Morio-Liondore, D Paddon-Jones, and RR Wolfe, Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle, J. Clin. Invest., 110:1687–1693, 2002. 84. Rasmussen, BB and WW Winder, Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase, J. Appl. Physiol., 83:1104–1109, 1997. 85. Ravussin, E, Metabolic differences and the development of obesity, Metabolism, 44:12–14, 1995. 86. Ren, JM, BA Marshall, EA Gulve, J Gao, DW Johnson, JO Holloszy, and M Mueckler, Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle, J. Biol. Chem., 268:16113–16115, 1993. 87. Rolfe, DF and GC Brown, Cellular energy utilization and molecular origin of standard metabolic rate in mammals, Physiol. Rev., 77:731–758, 1997.

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88. Roussel, R, PG Carlier, JJ Robert, G Velho, and G Bloch, 13C/31P NMR studies of glucose transport in human skeletal muscle, Proc. Natl. Acad. Sci. U.S.A., 95:1313–1318, 1998. 89. Ruderman, NB, AK Saha, D Vavvas, and LA Witters, Malonyl-CoA, fuel sensing, and insulin resistance, Am. J. Physiol., 276:E1–E18, 1999. 90. Saha, AK, TG Kurowski, and NB Ruderman, A malonyl-CoA fuel-sensing mechanism in muscle: effects of insulin, glucose, and denervation, Am. J. Physiol., 269:E283–289, 1995. 91. Schaffer, JE and HF Lodish, Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein, Cell, 79:427–436, 1994. 92. Schmitz-Peiffer, C, Protein kinase C and lipid-induced insulin resistance in skeletal muscle, Ann. N.Y. Acad. Sci., 967:146–157, 2002. 93. Schmitz-Peiffer, C, CL Browne, ND Oakes, A Watkinson, DJ Chisholm, EW Kraegen, and TJ Biden, Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat, Diabetes, 46:169–178, 1997. 94. Schmitz-Peiffer, C, ND Oakes, CL Browne, EW Kraegen, and TJ Biden, Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL49653, Am. J. Physiol., 273:E915–921, 1997. 95. Schrauwen, P and MK Hesselink, Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes, Diabetes, 53:1412–1417, 2004. 96. Schrauwen, P, WD van Marken Lichtenbelt, WH Saris, and KR Westerterp, Changes in fat oxidation in response to a high-fat diet, Am. J. Clin. Nutr., 66:276–282, 1997. 97. Shao, J, PM Catalano, H Yamashita, I Ruyter, S Smith, J Youngren, and JE Friedman, Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM, Diabetes, 49:603–610, 2000. 98. Shoyab, M, Long-chain fatty acyl-coenzyme A’s activate both the ligand-binding and protein kinase activities of phorboid and ingenoid receptor, Arch. Biochem. Biophys., 236:435–440, 1985. 99. Shulman, GI, Cellular mechanisms of insulin resistance, J. Clin. Invest., 106:171–176, 2000. 100. Simoneau, JA, SR Colberg, FL Thaete, and DE Kelley, Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women, FASEB. J., 9:273–278, 1995. 101. Simoneau, JA and DE Kelley, Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM, J. Appl. Physiol., 83:166–171, 1997. 102. Stremmel, W, G Strohmeyer, F Borchard, S Kochwa, and PD Berk, Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes, Proc. Natl. Acad. Sci. U.S.A., 82:4–8, 1985. 103. Tataranni, PA, IT Harper, S Snitker, A Del Parigi, B Vozarova, J Bunt, C Bogardus, and E Ravussin, Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure, Int. J. Obes. Relat. Metab. Disord., 27:1578–1583, 2003. 104. Tataranni, PA, DE Larson, and E Ravussin, Body fat distribution and energy metabolism in obese men and women, J. Am. Coll. Nutr., 13:569–574, 1994. 105. Tucker, MZ and LP Turcotte, Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake, Am. J. Physiol. Endocrinol. Metab., 285:E827–835, 2003.

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106. Turcotte, LP, JR Swenberger, MZ Tucker, and AJ Yee, Increased fatty acid uptake and altered fatty acid metabolism in insulin-resistant muscle of obese Zucker rats, Diabetes, 50:1389–1396, 2001. 107. Weyer, C, S Snitker, R Rising, C Bogardus, and E Ravussin, Determinants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects, Int. J. Obes. Relat. Metab. Disord., 23:715–722, 1999. 108. Young, ME, GW Goodwin, J Ying, P Guthrie, CR Wilson, FA Laws, and H Taegtmeyer, Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids, Am. J. Physiol. Endocrinol. Metab., 280:E471–479, 2001. 109. Youngren, JF, ID Goldfine, and RE Pratley, Decreased muscle insulin receptor kinase correlates with insulin resistance in normoglycemic Pima Indians, Am. J. Physiol., 273:E276–283, 1997. 110. Youngren, JF, ID Goldfine, and RE Pratley, Insulin receptor autophosphorylation in cultured myoblasts correlates to glucose disposal in Pima Indians, Am. J. Physiol., 276:E990–994, 1999. 111. Yu, C, Y Chen, GW Cline, D Zhang, H Zong, Y Wang, R Bergeron, JK Kim, SW Cushman, GJ Cooney, B Atcheson, MF White, EW Kraegen, and GI Shulman, Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle, J. Biol. Chem., 277:50230–50236, 2002. 112. Zhou, Q, PL Dolan, and GL Dohm, Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats, Mol. Cell Biochem., 194:209–216, 1999. 113. Zurlo, F, PM Nemeth, RM Choksi, S Sesodia, and E Ravussin, Whole-body energy metabolism and skeletal muscle biochemical characteristics, Metabolism, 43:481–486, 1994.

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Nonsurgical Management of Obesity Jarol Boan, M.D., M.P.H.

CONTENTS I. Introduction..................................................................................................99 II. Definition .....................................................................................................99 III. Relationship Between Obesity and Diabetes ............................................100 IV. Challenges of Lifestyle Change in the Management of Obesity .............101 V. The Role of Exercise in the Management of Obesity ..............................103 VI. The Role of Drugs.....................................................................................104 VII. Conclusion .................................................................................................105 References..............................................................................................................106

I. INTRODUCTION The rapid increase in the prevalence of overweight and obesity in the U.S. represents a major health problem. Obesity is a worldwide epidemic, and after tobacco use, obesity is the second-leading preventable cause of death in the U.S.1 Obesity is the result of sustained positive-energy balance, and the current obesity epidemic is the result of interactions between genes and the environment (i.e., diet and exercise habits), as well as metabolic, social, behavioral, and psychological factors. Obesity has been associated with three conditions that are characterized by resistance to insulin-mediated glucose disposal: coronary heart disease, type 2 diabetes, and hypertension.2,3 It has been estimated that approximately 25 percent of the U.S. population has three or more of the following abnormalities: excess body weight, high triglyceride or low HDL cholesterol concentration, hypertension, or impaired fasting glucose.4

II. DEFINITION Obesity is defined as an excess of fat in the body, which increases body weight beyond physical and skeletal requirements. Because total body fat is hard to measure, obesity is determined by the body-mass index (BMI). BMI is defined as weight divided by height squared (weight/height2) and represents the degree of body fat that a person has. A short person carries weight differently than a tall person, making 99

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TABLE 6.1 Weight Classification — Body Mass Index (BMI) Underweight Normal Overweight Obesity Class Obesity Class II Obesity, extreme

<18.5 18.5–24.9 25.0–29.0 30.0–39.0 35.0–39.9 >40.0

comparisons of weight between two individuals in a population difficult. The BMI is a concept of weight that estimates the degree of body fat independent of height, gender, or ethnicity. Since increasing BMI is associated with increasing risks for comorbidities, every physician should be familiar with the common cut-off points. These are presented in Table 6.1.

III. RELATIONSHIP BETWEEN OBESITY AND DIABETES It is often assumed that obesity equals insulin resistance, since overweight people tend to become more insulin sensitive with weight loss.5 However, results from the European Group for the Study of Insulin Resistance have shown that only 25 percent of people who are overweight had evidence of insulin resistance.6 Epidemiological evidence suggests that persons in the upper tertile of insulin resistance (measured by insulin-mediated glucose disposal) are at a statistically, significantly increased risk for developing type 2 diabetes, coronary heart disease, or hypertension.7,8 Recently, several well-designed clinical trials suggest that changes in lifestyle can prevent the onset of diabetes. In the Finnish Study, 522 obese (mean BMI 31 kg/m2) subjects were randomized to receive brief or individualized lifestyle instruction. After 3.2 years, there was a 58 percent relative reduction in the incidence of diabetes in the intervention group with individualized instruction.9 Diabetes Prevention Program is a multicenter, three-arm trial that randomized 3234 people at risk for diabetes to either a placebo pill or metformin plus minimal diet and exercise education (yearly individual sessions with handouts), or an intensive lifestyle intervention (diet, exercise, and behavioral education in a 16-lesson, 24-week curriculum, followed by monthly sessions, with both individual and group sessions).10 The intensive lifestyle group lost more weight (–5.6 kg versus –2.1 kg versus 0.1 kg) and had lower diabetes incidence (14.4 percent versus 21.7 percent versus 28.9 percent) than the metformin group and the control group, respectively. Interestingly, these results were seen even though only 50 percent of participants in the intensive group achieved the goal of 7 percent or more weight loss at 24 weeks, and only 58 percent were adherent to the exercise recommendation (150 minutes per week) at the most recent visit (mean follow-up 2.8 years). The intensive group successfully reduced energy intake by an average of 150–200 Kcal per day compared with the

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other groups. These studies emphasize the importance of measuring clinical outcomes (e.g., incidence of diabetes) because the intensive intervention might have been considered only mildly successful if only weight loss were measured.

IV. CHALLENGES OF LIFESTYLE CHANGE IN THE MANAGEMENT OF OBESITY Lifestyle change (diet and exercise) remain the first-line therapy for many common disorders, including diabetes, obesity, hypertension, and hyperlipidemia. The reported prevalence of people trying to lose weight in a community-based survey was 28.8 percent for men and 43.6 percent for women.11 A recent, systematic review of the literature regarding obesity treatment by McTigue et al. showed that behavior and counseling (diet and exercise) result in average weight loss of 3 kg to 6 kg over 12 to 60 months.12 Since dieting is associated with a high failure rate, physicians are hesitant to recommend it as a treatment for improving obesity comorbidities. However, a recent review of long-term outcomes of dietary intervention showed a 15 percent success rate among 2131 patients followed for five years.13 Interventions most likely to be successful were high intensity (contact with the participant more often than monthly) and included more than one component (i.e., diet education, exercise education, behavioral therapy). Educating the patient is the main goal of diet counseling, and effectiveness of learning is important for a patient to adhere effectively to a diet. Unfortunately, learning is quite difficult, given the complexities of nutrition information and of food choices available to a patient. Moreover, learning the healthiest food selections has never been as difficult as it is today when even renowned nutrition researchers stage debates in prominent medical journals over what types of foods should be eaten. Patients are often confused about what to eat. Despite multiple studies, clinical guidelines, and public recommendations in support of lowering dietary fat, evidence from a systematic review suggests that low-fat diets are no better than other types of weight-reducing diets in achieving and maintaining weight loss over a 12- to 18month period.14 Recently, greater weight loss and improvement in serum lipids have been reported with a low-carbohydrate/high-fat diet (Atkins-type diet).15,16 It is not surprising that patients receive streams of conflicting diet information from health professionals, friends, television, radio, newspapers, and magazines. Expanding a patient’s knowledge of nutrition is only one of the barriers to overcome when trying to improve lifestyle change. Other barriers to diet modification include resource constraints, environmental factors, and cultural/social factors. A healthy diet may be considered more expensive and time-consuming to prepare than a less-healthy diet. Similarly, low socioeconomic communities may have less access to healthy food options and more access to unhealthy food options. Even the wealthiest communities, however, are bombarded with the environmental pressures of unhealthy food options and advertising in today’s world. Intermingled among these issues are cultural, ethnic, and social factors, which can make healthy-diet changes very difficult for patients and challenge health practitioners trying to assist patients in these endeavors. As an example of culture’s powerful influence on diet, eating

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habits are one of the latest of the features assimilated from the new culture in individuals who relocate from one country to another.17 Meal size is another example of how social factors influence diet changes; the size of the meal is positively correlated with the number of people present at the meal.18 Behavioral or psychological issues may constitute some of the greatest barriers to modifying diet. With maturation, one’s eating habits become ingrained as a part of one’s behavior. In order for a patient to change eating behaviors, the patient must be motivated to do so. Similar to other lifestyle modifications, several psychological models can be used to assess patient motivation to change and predict success, including the stages-of-change (Transtheoretical),19 health belief,20 locus of control,21 and self-efficacy22 models. For some people, food is often used to relieve stress or adapt to difficult situations. When these behaviors become maladaptive, eating disorders might result. Not surprisingly, obese people have a higher prevalence of two distinct eating disorders: binge-eating syndrome and night-eating syndrome. Binge eating is a feeling of loss of control while consuming an amount of food that is larger than most people would eat. Binge eating is twice as prevalent in obese patients than nonobese patients.23 Moreover, relative to obese patients who do not binge eat, binge eaters have higher BMIs, as well as higher rates of comorbid depression and anxiety.24 Among bariatricsurgery patients, the prevalence of preoperative binge eating ranges from 13 percent to 49 percent.25 Night-eating syndrome, first recognized by Stunkard in 1955, is defined by ingestion of 50 percent of the daily caloric intake after the evening meal, awakening at least once a night for three nights a week to eat, and morning anorexia. In morbidly obese patients, the prevalence of night-eating syndrome may be as high as 26 percent.26 Dieting or chronic restrained eating may be important triggers for these disorders, which often go unrecognized due to the surreptitious manner in which patients binge. These disorders are complex psychological illnesses; further studies are needed to define appropriate therapy in obese patients with these problems. In addition to eating disorders, another psychological disorder that can be a barrier to lifestyle change is depression, especially in obese patients. Obese people are particularly vulnerable to symptoms of low self-esteem and depression, and depression has been linked strongly with nonadherence.35–37 Possible contributors to low self-esteem include repeated unsuccessful weight-loss attempts, failure to measure up to the thin ideal promoted by the media, discrimination, increased physical pain, and decreased physical ability.27 Health-care providers must be aware of the possibility of depressive symptoms in obese patients, and should avoid stereotyping their patients as having personality disorders responsible for their obesity. Health professionals are not immune to discrimination of obese people28; discrimination has even been demonstrated in obesity specialists.29 Therefore, when working with obese patients, it is important for health-care providers to maintain an empathetic attitude; avoid accusatory, derogatory, or nihilistic remarks; and rather, work with the patient to identify barriers to adherence and work to overcome these barriers. Two of the factors most consistently associated with successful weight loss include attendance at follow-up sessions and self-monitoring (of dietary intake and body weight).30 Another predictor, duration of intervention, is actually derived more

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by comparing longer duration interventions with shorter ones, as opposed to examining factors within one intervention. These factors are reflected in many current, successful interventions, which have frequent follow-up over long durations and emphasize patient involvement in monitoring, but also in menu and food preparation.

V. THE ROLE OF EXERCISE IN THE MANAGEMENT OF OBESITY The current public-health recommendation for physical activity is for individuals to participate in 30 minutes of moderately intense physical activity on most days of the week.31 The reason that people do not lose weight with increased exercise alone is because they usually also increase their food intake. Therefore, exercise combined with energy restriction is recommended based on the rationale that physical activity will result in an increase in total energy expenditure. It appears that the key factor that explains the relationship between exercise and weight is the adoption of an active lifestyle to prevent weight gain and weight regain. Exercise has a powerful effect on insulin sensitivity. Studies in Pima Indians and persons of European ancestry demonstrated that physical fitness was as powerful a modulator of insulin resistance as was body weight; each variable accounted for approximately 25 percent of the differences in insulin-mediated glucose disposal in nondiabetic persons.32 Obese individuals with type 2 diabetes mellitus had an increase in insulin sensitivity following low-intensity bicycle riding.33 In nonobese, insulin-resistant relatives of type 2 diabetic subjects, moderate-intensity exercise had a 40 percent increase in insulin sensitivity.34 The Diabetes Prevention Program found that intensive exercise in combination with a change in diet could lower the risk of progressing to diabetes by 58 percent.35 Despite recommendations of exercise for prevention of weight gain and improvement of cardiovascular fitness and insulin sensitivity, the major challenge is adoption of a regular exercise pattern. Recent studies on the effectiveness of intermittent exercise (multiple 10- to 15-minute exercise sessions daily) suggest that intermittent exercise is a successful strategy for increasing the adoption of exercise in overweight individuals who are sedentary.36 The long-term, cumulative effect of small changes in activity level can be beneficial. By walking about 2000 extra steps a day, 100 extra calories can be burned a day. It appears that the key factor that explains the relationship between exercise and weight is the adoption of an active lifestyle to prevent weight gain and weight regain. Evidence from the National Weight Control Registry, a group of 1047 individuals who lost at least 30 pounds (13.6 kg) and maintained that loss for at least one year, supports this claim. In an analysis of successful weight maintainers, one hour or more of moderate to vigorous physical activity per day was the factor that led to a successfully maintained weight loss over an average of 6.9 years.37 Understanding how powerfully the environment influences behavior is necessary to understand why some people gain more weight than others in the same environment. Considerable interindividual differences in the trainability of cardiorespiratory endurance traits have been observed after exposure to identical training programs,

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suggesting genetic diversity accounts for the variability in weight gain.38 In twin studies, Bouchard et al. showed that the effect of exercise may be influenced by genetic differences between individuals. In his elegant studies, there was a 6.8 times greater change in body weight between pairs than within pairs of twins that were engaging in the same type and amount of physical activity.39 Energy expended during physical activity is highly variable, and it is the component of total energy expenditure over which an individual has the most control. It may represent 15 percent to 50 percent of the total 24-hour energy expended, depending on the activity of the individual. Increasing intensity and duration of activity will increase energy expenditure.

VI. THE ROLE OF DRUGS Weight-loss medications are indicated for patients with a BMI greater than 30 kg/m2 (27 kg/m2 with comorbidities) who have not achieved weight loss with lifestyle changes. Presently, two drugs (orlistat and sibutramine) are FDA approved and marketed as adjunctive treatment of obesity, albeit many compounds are being studied for the treatment of obesity. The pharmacological treatment of obesity receives substantial attention from research and development. It is estimated that the market for obesity treatments in the United States ranges from $735.5 million to $1.23 billion. One study has shown that sibutramine has helped obese patients on a four-week, very low-calorie diet maintain their weight loss for a period of 12 months.40 In the Sibutramine Trial in Obesity Reduction and Maintenance (STORM), 605 patients were followed for 24 months. Eighty-two percent of the patients on sibutramine achieved at least a 5 percent weight reduction and were able to maintain it for 18 months compared to 16 percent of patients on placebo.41 Predictors of an effective response with the use of sibutramine include a history of successful weight loss with lifestyle change alone, a patient who struggles with recognition of signals for hunger and fullness, and a patient who admits to feelings of a lack of control over food intake. The drug orlistat has also been shown to be an effective obesity medication. Orlistat works by inhibiting absorption of approximately 30 percent of dietary fat from the small intestine. In a double-blind, randomized-controlled trial of obese patients with orlistat 120 mg (three times a day) or placebo for one year in conjunction with the hypocaloric diet (600 Kcal/day deficit), Sjostrom et al. found that the orlistat group lost more body weight than the placebo group (10.2 percent versus 6.1 percent; least squared means (LSM) difference 3.9 kg, p < 0.001).42 The following group of patients has a superior response to orlistat: those with an inability to identify hidden fat in foods, those with significant restaurant eating, and those seeking negative reinforcement. Several new drugs show promise for future treatment of obesity. Axokine, a genetically engineered recombinant human variant ciliary neurotrophic factor that signals through leptinlike pathways in the hypothalamus, has been shown to bypass leptin resistance.43 Topiramate is a broad-spectrum anticonvulsant that stimulates [gamma]-aminobutyric acid activity. In a 14-week, double-blind trial comparing

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topiramate to placebo, topiramate was associated with a significant reduction in binge frequency, binge-day frequency, body-mass index, and weight.44 Zonisamide, an antiepileptic drug that has serotonergic and dopaminergic activity, has been shown to produce weight loss in randomized-controlled trials (drug versus placebo 9.2 kg versus 1.5 kg over 32 weeks).45 Glucagon-like peptide-1 (GLP-1) has been shown to be effective to stimulate insulin secretion, suppress glucagon secretion, and inhibit gastric emptying.46 Rimonabant, a Cannabinoid CB1 agonist, has been shown to be effective in weight loss in both animal models47 and early clinical trials.48 The pharmacological treatment of obesity continues to receive substantial attention from the pharmaceutical industry, and newer drugs may be marketed in the near future.

VII. CONCLUSION Controlling intake and increasing activity (dieting and exercise) are very difficult, and it is important for physicians to understand that some patients may have to do much more than others to maintain a healthy weight. There are windows of opportunity when radical behavioral changes seem to work. For example, after a diagnosis of diabetes or myocardial infarction, patients are often highly motivated to undertake behavioral changes. Unfortunately, the amount of weight loss by nonsurgical approaches rarely surpasses 15 percent from baseline weight. Table 6.2 provides some guidelines for improving adherence to dietary changes. It is important that physicians not take nonadherence to their suggestions personally and criticize patients when they don’t achieve their weight goals. After validating the difficulties that their patients face, it is important for physicians to focus on identifying obstacles and help their patients design a plan to succeed the next time.

TABLE 6.2 Practical Strategies for Improving Diet Adherence Use self-monitoring (e.g., diet records, weighing) Identify and employ alternatives to eating (e.g., exercise, hobbies) Find a partner(s) to diet with you Avoid triggers for eating (especially high-risk foods) Keep acceptable foods accessible and unacceptable foods inaccessible Keep a regular eating schedule and eat frequent small amounts rather than infrequent binges Practice responses to hosts/acquaintances that urge you to indulge or eat more Follow an eating schedule Use a shopping list and stick to the list Do not grocery shop when hungry Be involved in food preparation Eat slowly Do not feel compelled to clean your plate Indulge infrequently in small amounts After losing weight, give away or sell clothes that are too big Realize that lapses will occur and return to diet after lapses

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In fact, better adherence to diet recommendations would greatly reduce the morbidity and mortality associated with obesity and diabetes. For a number of factors, adherence to diet can be difficult and restrictive. This results in both patients and practitioners frequently abandoning diet interventions in favor of medications and even surgery, despite the many adverse effects and complications, not to mention cost, inherent to these therapies. Predictors of poor outcome include prior attempts at weight loss, poor health, psychiatric illness, and multiple life stressors.49, 50 Patients with these factors should therefore be targeted for more aggressive and supportive interventions to improve their chances of success. The future of obesity treatment involves a multidisciplinary approach that encompasses medical interventions, pharmaceutical developments, and surgical approaches in combination with broad societal changes (school-based programs, workplace programs, food industry and media involvement). Since sustained weight loss by lifestyle change is difficult to achieve, preventing weight gain should be the focus of these changes. Unfortunately, over the last three decades, childhood obesity has more than doubled for children aged 2–5 years and adolescents aged 12–19 years, and it has tripled for children 6–11 years.51 A substantial amount of research examining valid and sustainable treatment options is required.

REFERENCES 1. Allison DB, Fontaine, KR, Manson, JE, Stevens, J, and VanItallie, TB, Annual deaths attributable to obesity in the United States, JAMA, 282(16):1530–1538, 1999. 2. Reaven, GM, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes, 37:1595–607, 1988. 3. Reaven, GM, Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease: Syndrome X revisited, in Handbook of Physiology, Jefferson, LS and Cherrington, AD, Eds., Oxford University Press, New York, 2001, Sec. 7, The Endocrine System, Vol 2, The Endocrine Pancreas and Regulation of Metabolism, p. 1169–97. 4. Ford, ES, Giles, WH, and Dietz, WH, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA, 287:356–9, 2002. 5. Olefsky, J, Reaven, GM, and Farquhar, JW, Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects, J. Clin. Invest., 53:64–76, 1974. 6. Ferrannini, E, Natali, A, Bell, P, Cavallo-Perin, P, Lalic, N, and Mingrone, G, Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR), J. Clin. Invest., 100:1166–73, 1997. 7. Yip, J, Facchini, FS, and Reaven, GM, Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J. Clin. Endocrinol. Metab., 83:2773–6, 1998. 8. Facchini, FS, Hua, N, Abbasi, F, and Reaven, GM, Insulin resistance as a predictor of age-related diseases, J. Clin. Endocrinol. Metab., 2001;86:3574–8, 2001. 9. Tuomilehto, J, Lindstrom, J, Eriksson, JG, et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N. Engl. J. Med., 344(18):1343–1350, 2001.

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10. Knowler, WC and Nathan, DM, Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346(6):393–403, 2002. 11. Serdula, MK, Mokdad, AH, Williamson, DF, Galuska, DA, Mendlein, JM, and Heath, GW, Prevalence of Attempting Weight Loss and Strategies for Controlling Weight, JAMA, 282:1353–1358, 1999. 12. McTigue, KM, Harris, R. Hemphill, B, Lux, L, Sutton, S, Bunton, AJ, and Lohr, KN, Screening and interventions for obesity in adults: summary of the evidence for the U.S. Preventive Services Task Force, Ann. of Intern. Med., 139(11):933–49, 2003. 13. Ayyad, C and Anderson, T, Long-term efficacy of dietary treatment of obesity: a systematic review of studies published between 1931 and 1999, Obes. Rev., 1:113–119, 2000. 14. Thompson, RL, Summerbell, CD, Hooper, L, et al., Relative efficacy of differential methods of dietary advice: a systematic review, Am J Clin Nutr., 77(Suppl. 4):1052S–1057S, 2003. 15. Katan, MB, Grundy, SM, and Willett, WC, Should a low-fat, high-carbohydrate diet be recommended for everyone? Beyond low-fat diets, N. Engl. J. Med., 337(8):563–566; discussion 566–567, 1997. 16. Foster, GD, Wyatt, HR, Hill, JO, Mcguckin, BG, Brill, C, Mohammed, S, Szapary, PO, Rader, DJ, Edman, JE, Klein, S, A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348:2082–90, 2003. 17. Brownell, KD and Cohen, LR, Adherence to dietary regimens. 1: An overview of research, Behav. Med., 20(4):149–154, 1995. 18. De Castro, JM and de Castro, ES, Spontaneous meal patterns of humans: influence of the presence of other people, Am. J. Clin. Nutr. 50(2):237–247 1989. 19. DiClemente, CC and Prochaska, JO, Self-change and therapy change of smoking behavior: a comparison of processes of change in cessation and maintenance, Addict. Behav., 7(2):133–142, 1982. 20. Becker, M, The health belief model and personal health behavior, Thorofare, NJ, Stock; 1974. 21. Wallston, K and Wallston, B, Development of the multidimensional health locus of control (MHLC) scales. Health Educ. Monogr., 6:160–170, 1978. 22. Bandura, A, Self-efficacy: toward a unifying theory of behavioral change, Psychol. Rev., 84:191–215, 1977. 23. Smith DE, Marcus MD, Lewis CE, Fizgibbon M, Schreiner P, Prevalence of binge eating disorder, obesity, and depression in a biracial cohort of young adults, An. Behav. Med., 20(3):227–232, 1998. 24. Wadden, Womble, Stunkard, Anderson, Psychosocial consequences of obesity and weight loss, in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ Eds., Guilford Press, New York, 2002. 25. Powers, PS, Perez, A, Boyd, F, and Rosemurgy, A, Eating pathology before and after bariatric surgery: a prospective study, Int, J. Eat. Disord., 25:293-300, 1999. 26. Rand CS, Macgregor AM, Stunkard AJ. The night eating syndrome in the general population and among post-operative obesity surgery patients, Int. J. Eat. Disord., 22:65–69, 1997. 27. Allon, N, The stigma of overweight in everyday life, in Psychological Aspects of Obesity: A Handbook, Wolman, B, Ed., New York, Van Nostrand Reinhold, New York, 1982, p. 130–174. 28. Kaminsky, J and Gadaleta, D, A study of discrimination within the medical community as viewed by obese patients, Obes. Surg., 12(1):14–18, 2002.

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29. Schwartz, MB, Chambliss, HO, Brownell, KD, Blair, SN, and Billington, C, Weight bias among health professionals specializing in obesity, Obes. Res., 11(9):1033–1039, 2003. 30. Wing, RR, Behavioral weight control in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ, Eds., Guilford Press, New York, 2002. 31. Pate, RR, Pratt, SN, Blair, S, et al., Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine, JAMA, 273:402–407, 1995. 32. between degree of obesity and in vivo insulin action in man, Am. J. Physiol., 1985:248:E286–91, 1985. 33. Usui, K, Yamanouchi, K, Asai, K, Yajima, M, Iriyama, A, Okabayashi, N, Sakakibara, H, Kusunoki, M, Kakumu, S, and Sato, Y, The effect of low intensity bicycle exercise on the insulin-induced glucose uptake in obese patients with type 2 diabetes, Diabet. Res. Clin. Pract., 41(1):57–61, 1998. 34. Perseghin, G, Price, TB, Petersen, KF, Roden, M, Cline, GW, Gerow, K, Rothman, DL, and Shulman, GI, Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects, N. Engl. J. Med., 335(18):1357–62, 1996. 35. Knowler, WC and Nathan, DM, Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346(6):393–403, 2002. 36. Jakicic, JM, Wing, RR, Butler, BA, and Robertson, RJ, Prescribing exercise in multiple short bouts versus one continuous bout: effects on adherence, cardiorespiratory fitness, and weight loss in overweight women, Int. J. Obes., 1995; 19:893–901, 1995. 37. McGuire, MT, Wing, RR, Klem, ML, Seagle, HM, and Hill, JO, Long term maintenance of weight loss: Do people who lose weight through various weight loss methods use different behaviors to maintain their weight? Int. J. Obes., 1998; 22(6):572–577, 1998. 38. Bouchard, C, Individual differences in the response to regular exercise, Int. J. Obes. Relat. Metab. Disord., 4:5–8, 1995. 39. Bouchard, CA, Tremblay, A, and Despres, JP, The response to exercise with constant energy intake in identical twins, Obes. Res., 1994; 5:400–410, 1994. 40. Apfelbaum, M, et al., Am. J. Med., 106:179, 1999. 41. Apfelbaum, M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E, Long-term maintenance of weight loss after a very low calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am. J. Med., 106(2):179–184, 1999. 42. James, WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF, Effect of sibutramine on weight maintenance after weight loss: a randomized trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 356(9248):2119–2125, 2000. 43. SB, Bray, GA, Roberts, WG, Heyman, ER, Stambler, N, Heshka, S, Vicary, C, and Guler, HP, Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study, JAMA, 289(14):1826–32, 2003. 44. McElroy, SL, Arnold, LM, Shapira, NA, Keck, PE, Jr. Rosenthal, NR, Karim, MR, Kamin, M, and Hudson, JI, Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial, Am. J. Psychiat., 160(2):255–61, 2003.

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45. Gadde, KM, Franciscy, DM, Wagner, HR, 2nd, and Krishnan, KR, Zonisamide for weight loss in obese adults: a randomized controlled trial, JAMA, 289(14):1820–5, 2003. 46. Kolterman, OG, Buse, JB, Fineman, MS, Gaines, E, Heintz, S, Bicsak, TA, Taylor, K, Kim, D, Aisporna, M, Wang, Y, and Baron, AD, Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes, J. Clin. Endocrinol. Metab., 88(7):3082–9, 2003. 47. Hildebrandt, AL, Kelly-Sullivan, DM, and Black, SC, Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice, Eur. J. Pharmacol., 462(1–3):125–32, 2003. 48. Black, SC, Cannabinoid receptor antagonists and obesity, Curr. Opin. Invest. Drugs, 5(4):389–94, 2004. 49. Perri, MG, McAdoo, WG, and McAllister, DA, Effects of peer support and therapist contact on long-term weight loss, J. Consult. Clin. Psychol., 55:615–617, 1987. 50. Wing, RR, Behavioral weight control, in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ, Eds., Guilford Press, New York, 2002. 51. National Academy of Science, Preventing Childhood Obesity: Health in the Balance Fact Sheet, September 2004.

7

Bariatric Surgery for Obesity Ross L. McMahon, M.D., F.R.C.S.C., FACS

CONTENTS I. Introduction................................................................................................111 II. Definitions and Risk Factors .....................................................................112 III. Surgical Treatment of Morbid Obesity .....................................................112 A. History ...............................................................................................112 B. Current Surgical Therapies for Morbid Obesity...............................114 1. Patient Selection ..........................................................................114 2. Laparoscopic Adjustable Gastric Banding..................................115 3. Gastric Bypass.............................................................................117 4. Biliopancreatic Diversion............................................................119 IV. Laparoscopic Bariatric Surgery.................................................................120 V. Conclusion .................................................................................................121 References..............................................................................................................121

I. INTRODUCTION Obesity has become a major health problem in the United States. Nearly two-thirds of U.S. adults are overweight (BMI ≥ 25).1 This represents 129.6 million American adults. Of these, 61.3 million are obese (BMI > 30), and it is estimated that 4 million are severely obese, and 1.5 million are morbidly obese.2,3 From 1960 to 1990, the incidence of obese American adults increased from 13 percent to 35 percent.4 This rapid rise in the prevalence of obesity has occurred despite multiple public-health efforts and in the backdrop of a culture that spends $30 billion annually on commercial weight-loss products.5 Not only is obesity a significant public-health challenge, it is an enormous economic burden. Obese patients are at increased risk of multiple medical comorbidities: coronary-artery disease, hypertension, type 2 diabetes, respiratory insufficiency, venous stasis or thromboembolic disease, debilitating arthritis of weightbearing joints, and depression, as well as uterine, ovarian, colon, breast, and prostate cancer.6 The annual health-care expenditures for obesity-related diseases in the United States have increased from $39 billion in 1993 to more than $75 billion now and represent more than 5 percent of total annual health-care costs.7 111

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II. DEFINITIONS AND RISK FACTORS In 1998, the National Institutes of Health established federal guidelines for the identification, evaluation, and treatment of overweight and obese adults.8 Ideal-bodyweight (IBW) tables are based on actuarial studies performed by the Metropolitan Life Insurance Company.9 The amount a patient is overweight has been categorized based on body-mass index (BMI), which normalizes the weight with the patients height. Overweight is defined by having a BMI greater than 25 kg per m2, obesity is having a BMI greater than 30 kg per m2, severe obesity is having a BMI greater than 35 kg per m2, and morbid obesity is having a BMI greater than 40 kg per m2 or a BMI greater than 35 kg per m2 with concomitant obesity-related morbidity. A BMI of 40 kg per m2 roughly correlates with an actual weight exceeding ideal body weight by 100 pounds. Federal guidelines based on studies relating BMI to morbidity and mortality have been released. Patients with a BMI between 20 and 25 kg per m2 have the lowest mortality rate.10 As BMI increases above 25 kg per m2, mean blood pressure and total blood cholesterol increase, and mean high-density lipoprotein levels decrease.11 Women with a BMI greater than 29 kg per m2 have a significantly increased incidence of myocardial infarction.12 Obese patients have an increased risk of coronary-artery disease.13,14 Complications related to obstructive sleep apnea are twelvefold to thirtyfold higher in the morbidly obese than in the general population.15 The most significant observation is that morbidly obese patients who are 20 to 40 years of age may experience a twelvefold reduction in life expectancy in comparison with age-matched control subjects. These observations confirm the concept that obesity has become a national health crisis. Once classified, it is recommended that patients who are obese or severely obese be treated medically with caloric restriction, increased physical activity, Food and Drug Administration approved weight-loss drugs, and behavioral modification. Surgery is recommended for patients who are morbidly obese or for those who are severely obese with concomitant obesity-related diseases.

III. SURGICAL TREATMENT OF MORBID OBESITY A. HISTORY Weight loss in relation to intestinal resection was observed in the late 19th century. Trzebicky16 first noted nutritional imbalances in canines following proximal and distal small-bowel resection. Weight loss in humans after gastric or small-intestinal resection was reported by Von Eiselsberg in 1895.2 Jensenius demonstrated that after distal small-bowel resection in a canine model, there was an increased loss of fat in the stool. Kremen later demonstrated that resection of greater than 50 percent of the distal small-intestine reduced fat absorption and resulted in weight loss, whereas lesser resections of proximal small intestine resulted in normal nutritional balance. Based on this work, Kremen performed the first therapeutic bariatric procedure, an end-to-end jejunoileostomy, in 1954. In 1955, Payne and Dewind performed the first clinical trial of obesity surgery. This trial of an intestinal bypass procedure was

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abandoned due to severe metabolic disturbances, liver failure, and protein-calorie malnutrition.17,18 The procedure was subsequently modified by anastomosing the proximal jejunum to the distal ileum, with the bypassed segment of small bowel anastomosed end-to-side to the colon, known as the jejunoileal bypass. This procedure was popular in the 1960 to 1970 era, and was very effective for weight loss. However, weight loss was complicated by significant electrolyte imbalances, vitamin deficiencies, intractable diarrhea, cholelithiasis, urolithiasis, neuromyopathies, and liver failure. As many as 25 percent of these patients required reversal of the jejunoileal bypass because of these complications, and the procedure was eventually abandoned.19 Mason and Ito developed the gastric bypass procedure for weight loss in the 1960s. Their work was based on the observation by Von Eiselsberg that weight loss often followed hemigastrectomy. In their report, 24 patients who had undergone Billroth II retrocolic gastrojejunostomy to a 100 ml gastric pouch with a 2 cm gastric outlet lost an average weight of 60 pounds at 18 months' follow-up.20 Electrolyte and vitamin deficiencies were manageable with supplementation, and liver dysfunction was unusual. In order to prevent bile reflux gastritis, Griffen modified the procedure by constructing a Roux-en-Y gastrojejunostomy instead of a Billroth II anastomosis.21 Even though many variations of the original procedure have been described, gastric bypass with a Roux-en-Y gastrojejunostomy remains an effective weight-loss operation with an acceptable complication rate.22 The era of purely restrictive procedures for the treatment of obesity came in 1971, when Printen and Mason introduced restrictive gastroplasty procedures.23,24 Gastroplasties were initially performed by partitioning the proximal stomach with a stapler, leaving a small (1 cm) gastric outlet along the greater curve. The staples were expected to hold the partition and opening in place for the lifetime of the patient. This would prove to be overly optimistic. The staple line frequently disrupted over 2 to 5 years with either the small gastric outlet dilating or the partition entirely failing. The end result was the same: Many patients lost significant amounts of weight only to regain it. Stapling and other surgical technologies continued to evolve over this time period. In 1982, Mason created a 2.5 cm circular defect with an endto-end anastomosis (EEA) stapler approximately 8 to 9 cm below the angle of His and 3 cm from the lesser curve, and a polypropylene mesh collar was placed around the gastric outlet.25 The era of malabsorption returned in 1981, when Scopinaro and coworkers26 in Italy reported their initial results with biliopancreatic bypass (BPD). The BPD combines a subtotal gastrectomy with a Roux-en-Y gastroileal anastomosis and a jejunoileal anastomosis 50 cm proximal to the ileocecal valve to allow absorption of nutrients in the distal 50 cm common channel. Results reported by Scopinaro and coworkers have been excellent, with reduction in excess weight of nearly 75 percent. Complications associated with the procedure are protein malnutrition and malabsorption of vitamins; severe complications, such as liver failure, are rare, but they do occur. To reduce these complications, Marceau and associates27 in Canada modified the technique of Scopinaro and developed the biliopancreatic diversion with a duodenal switch (BPD-DS). It is constructed by performing a sleeve gastrectomy instead of subtotal gastrectomy, a Roux-en-Y duodenoileal anastomosis, and an

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ileoileal anastomosis 100 cm proximal to the ileocecal valve. Excellent results have been reported, and malabsorption complications have been less significant. Another commonly performed restrictive procedure is adjustable gastric banding (AGB). The banding devices, usually made of silicone, compartmentalize the proximal stomach into a small pouch.28 There is currently one FDA-approved device for sale in the USA, Inamed’s Lap-Band. AGB was first introduced in the 1990s.29 The adjustable band has a saline-injectable, subcutaneous reservoir that is tunneled in the subcutaneous tissue of the abdominal wall and connected to an inflatable silicone band that is wrapped around the proximal stomach. If weight loss is inadequate or symptoms of outlet obstruction arise, the silicone band can be inflated or deflated with saline, thereby changing the size of the gastric restriction. Not long after the introduction and rapid acceptance of laparoscopic cholecystectomy, surgeons began performing laparoscopic bariatric procedures. Chelala30 and Belachew31 and their colleagues reported performing laparoscopic adjustable gastric banding in 1992. Laparoscopic Roux-en-Y gastric bypass and laparoscopic verticalbanded gastroplasty were reported in 1993 by Wittgrove32 and Lonroth33 at different institutions. Initial results of laparoscopic bariatric surgery have validated its safety and feasibility.33,34 In summary, bariatric surgery evolved over the second half of the 20th century. Even though the ideal procedure has yet to be devised, surgery has emerged as the most effective treatment for sustained, significant weight loss in the morbidly obese.

B. CURRENT SURGICAL THERAPIES

FOR

MORBID OBESITY

1. Patient Selection In keeping with the National Institutes of Health Consensus Development Conference Statement on Gastrointestinal Surgery for Morbid Obesity, patients with a BMI exceeding 40 kg per m2 or 35 kg per m2 with obesity-related comorbidities are candidates for the surgical treatment of morbid obesity.10 Surgery for morbid obesity should be offered to patients who are well-informed and motivated, and who are acceptable to operative risks. Patients should be evaluated preoperatively by a multidisciplinary team of nutritionists, nurse clinicians, internists, psychologists or psychiatrists, and surgeons. Patients should be screened for common obesity-related conditions, and these conditions should be optimized. Tests to be considered are chest x-ray; electrocardiography, cardiac stress testing, and echocardiography for cardiac disorders; arterial blood-gas and pulmonary-function testing, with arterial blood gases for the hypoventilation syndrome and polysomnography for the sleep apnea syndrome; barium swallow; TS, lipid panel, HbA1c, and fasting blood sugar. The choice of procedures with risks and benefits must be clearly explained to the patient, as should be the need for long-term follow-up. The optimal operation is still a matter of much discussion. In reality, careful patient selection can result in a close match between operation and patient. This also includes the very real and not-too-infrequent denial of any surgical option for the inappropriate surgical candidate. The most commonly performed surgical procedures in the U.S. are the Lap-Band, the Roux en Y gastric bypass, and the bilopancreatic diversion.

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2. Laparoscopic Adjustable Gastric Banding The operation is performed almost exclusively laparoscopically. There are several variations in port placement and number, but five or six incisions are usually necessary. The band is introduced in its open form. The stomach is exposed, and a retrogastric tunnel is created from the lesser curve side of the inferior border of the hiatus to the angle of His with a Lap-Band passer tool. This tool is then articulated at the angle of His to create the tunnel. The Lap-Band is threaded into the eye of the tool, which is then dearticulated and brought back through the tunnel to the lesser curvature side. The band is partially closed and a sizing balloon introduced. The band is closed with the sizing balloon in place to ensure the band is not too tight. If the band is adequately free, then the balloon is deflated and removed. If the band is too tight, fat in this area needs to be removed to prevent postoperative obstruction. A retaining flap is then created anteriorly by plicating the stomach to itself over the band with three to four interrupted sutures. The tubing is then brought out of the abdominal wall and the port secured to the rectus sheath35 (Figure 7.1). Interpretation of outcome data for LAGB is fraught with difficulty. This is due to a number of factors. The results seem to have come full circle. All of the longterm data are from outside the U.S., and these data seem quite positive for the device. However, the original U.S. FDA trials are in striking contrast to the world literature. The operation has subsequently been modified to avoid problems, and the most recent reports from U.S. centers36–38 seem to be in line with the results from other world centers, such as Australia.39-41 To avoid confusing less-than-optimal techniques and to best present current knowledge and technique, the most recent U.S. reports

FIGURE 7.1 Gastric banding. A saline-injectable locking gastric band placed around the proximal stomach. The reservoir is buried subcutaneously and sutured to the anterior rectus sheath.

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TABLE 7.1 Adverse Events Following Laparoscopic Adjustable Gastric Banding (n = 445) Adverse Event

†

n (%)

Perioperative Death Malignant hyperthermia Splenectomy Stoma obstruction Device-related Tubing disconnection/leak Port infection Port migration Delayed Gastric prolapse Erosion Explanation †

† † † † † † † † † † † † † Total

† 1 (0.2%) 1 (0.2%) 1 (0.2%) 12 (2.7%) † 4 (0.9%) 5 (1%) 4 (0.9%) † 14 (3%) 1 (0.2%) 4 (0.8%) 47 (10.5%)

are the best indicators of this procedure’s true potential. For longer-term data, the Australian series seems most suited for comparison. In the U.S. series by Ren and colleagues, a total of 445 patients underwent LAGB using the Lap-Band.42 There were 341 female and 103 male individuals with an average age of 42.1 years and an average BMI of 49.6 kg/m2. Average body weight was 299.4 lb. Conversion to laparotomy was necessary in one patient (0.2 percent) because of splenic bleeding. One operation was aborted due to extreme hepatomegaly in a male patient with BMI = 43, excessive bleeding, and nonvisualization of the gastroesophageal junction. Mean length of hospital stay was 1.1 days. Adverse events occurred in 10.5 percent of patients (Table 7.1). The one death occurred in a patient who experienced sudden cardiac arrest the afternoon after surgery from a presumed arrhythmia. Acute postoperative stoma obstruction was felt to be secondary to presumed gastric-wall edema or hematoma and usually responded to conservative management. Intravenous hydration was required in seven patients. Four patients (1.1 percent) required laparoscopic revision to remove perigastric fat incorporated within the band, and one patient required laparoscopic band explantation. All postoperative stoma obstructions occurred in the first 125 operations performed by one surgeon. The procedure was modified with removal of perigastric fat to minimize the amount of fat incorporated within the band, which caused external gastric compression and, subsequently, obstruction. No acute stomal obstructions occurred thereafter. There were no known cases of thromboembolism, myocardial infarction, or intestinal sepsis. There were 13 (3 percent) reservoir port-related complications. There were five patients with port infection requiring removal of the ports. The ports were reimplanted three to six months after removal. Gastric prolapse, or band slippage, occurs when the stomach slides up

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through the band, displacing the band and causing obstruction. In this series, gastric prolapse was treated by repositioning or replacement of the Lap-Band. Band erosion occurred in one patient, and that band was removed. Two bands were explanted because of intraabdominal abscesses. There has been no evidence of esophageal dilatation. Four patients were lost to follow-up, and 99 of the 445 were available for one-year review. The average percent excess weight loss (EWL) at 12 months after Lap-Band surgery was 44.3 percent ± 17 (range 6.5–92 percent). In an earlier report, Rubinstein showed 38 percent EWL at one year after LAGB, yet achieved 54 percent EWL by three years.38 Ren and colleagues’ one-year data match that of the large series from two Australian centers, as reported by Fielding et al.41 and O’Brien39,40 Achieving successful weight loss with LAGB seems to lie with both surgical technique and patient follow-up with band adjustments. Weight loss at one year in this series is slightly less than that commonly reported for RYGB.29,32 However, over time, weight loss appears to continue in patients who have undergone a gastric band, such that three- and five-year data result in a comparable percentage of EWL.39–41. The Lap-Band is presently the safest available surgical procedure to treat morbid obesity. It seems to be, at least in the short term, as effective as other surgical alternatives. 3. Gastric Bypass This procedure is highly suited to performance through a laparoscopic approach. The open approach, however, is still used in many centers. Whether done open or laparoscopically, the steps of the procedure are the same. The operation can be divided into distinct steps: Step one, creation of the roux limb: The ligament of Treitz is identified; approximately 40 cm distal to the ligament is measured; the small bowel is divided at this position; the small-bowel mesentery is then divided; the small bowel to be bypassed, 75 cm–150 cm, depending on anatomy and amount of malabsorption, if any, desired, is then measured; the enteroenterostomy is constructed; and the defect in the mesentery closed. Step two, division of the omentum: The space between the roux limb and the transverse mesocolon — Peterson’s space — a potential space for an internal hernia, is closed. Step three, creation of the gastric pouch: The avascular window in the gastrohepatic omentum is incised and opened along the lesser curve of the stomach, and the fatty and vascular tissue divided from the gastric wall, to create a 30 ml pouch; one transverse staple firing and two to three vertical firings create the pouch; the roux limb is then anastomosed to the pouch to complete the procedure; and a drain is placed across the upper anastomosis (Figure 7.2). The long-term results of the Roux-en-Y gastric bypass on weight loss and improvement in obesity-related comorbidities have been described by a number of authors. Pories and colleagues43 have described their results over a 14-year period with a 97 percent follow-up in 608 morbidly obese patients. The mean weight loss was 49.2 percent (99.7 pounds) of excess body weight. A more striking finding in this study was the long-term control of adult-onset diabetes. Of 298 glucose-intolerant patients (146 with noninsulin-dependent diabetes mellitus and 152 with

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FIGURE 7.2 Roux-en-Y gastric bypass. A Roux limb, created by dividing the proximal jejunum 40–60 cm distal to the ligament of Treitz, is anastomosed end-to-side to a 30-ml gastric pouch. The proximal jejunal (biliopancreatic) limb is anastomosed end-to-end to the Roux limb 75–150 cm distal to the gastroenterostomy.

impaired glucose tolerance), 271 (91 percent) maintained normal fasting glucose levels, glycosylated hemoglobins, and insulin levels. Of the diabetic patients, 80 percent were off all hypoglycemic agents. Although the mechanism remains unclear, the results have been reproduced in a number of shorter-term studies. In 353 patients with hypertension, only 85 (14 percent) remained hypertensive. Other studies report significant reductions in blood pressure, triglycerides, and low-density lipoproteins, with an increase in the plasma levels of high-density lipoproteins.44 Complications of open gastric bypass include splenic injuries (0.7 percent to 2.5 percent), anastomotic leaks (1.2 percent to 5 percent), seromas or superficial wound infections (11.4 percent to 14.5 percent), deep-wound infections (3 percent to 4.4 percent), deep venous thrombosis or pulmonary embolisms (0.6 percent to 2 percent), and a 30-day mortality rate of approximately 0.4 percent.45,46 Although the leak and coagulation complications remain with the laparoscopic approach, the wound problems and splenic-injury problems have declined significantly. Late complications include gastric-outlet stenosis and obstruction (3.4 percent to 14.6 percent), marginal ulcer (0.2 percent to 13.3 percent), small-bowel obstruction (4.7 percent), incisional hernia (4.7 percent to 23.9 percent), and symptomatic gallbladder disease (10 percent to 11.4 percent).47–49 The incisional hernia rate with the laparoscopic approach is significantly reduced. Nutritional deficiencies of iron, vitamin B12, folate, calcium, and the fatsoluble vitamins A, D, and E can occur without appropriate supplementation. Currently Roux-en-Y gastric bypass is the gold standard weight-loss operation with good long-term follow-up studies.50

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4. Biliopancreatic Diversion Biliopancreatic bypass is performed either laparoscopically or through a midline incision. A subtotal gastrectomy is performed, leaving a proximal gastric remnant of 200 to 500 ml. The ileum is transected 250 cm proximal to the ileocecal valve. The distal ileal limb is brought through a retrocolic opening in the transverse mesocolon and anastomosed to the gastric pouch. The biliopancreatic or proximal limb is anastomosed end-to-side to the distal ileum, 50 cm proximal to the ileocecal valve. This results in a 50 cm common channel between the two limbs (Figure 7.3). A modification of this technique is the biliopancreatic bypass with a duodenal switch (BPD-DS).51,52 The greater curvature of the stomach is resected to create a lesser curvature gastric sleeve (sleeve gastrectomy). This reduces the gastric volume to 200 ml to 500 ml, equivalent to a subtotal gastrectomy, and maintains the integrity of the vagus nerves. The duodenum is transected 5 cm distal to the pylorus. The ileum is transected 250 cm proximal to the ileocecal valve, and the distal ileal limb is anastomosed end-to-end to the proximal duodenum. The biliopancreatic limb is anastomosed end-to-side to the distal ileum, 100 cm proximal to the ileocecal valve, resulting in a 100 cm common channel between the two limbs. There are significant reports of the outcomes after BPD and BPD-DSs from Italy and Canada, but fewer have been reported in the U.S. Scopinaro and colleagues53 at the University of Genoa, Italy, published results for 1356 patients undergoing

FIGURE 7.3 Biliopancreatic bypass with a duodenal switch. The greater curvature

of the stomach is resected to create a sleeve gastrectomy. After dividing the duodenum 5 cm distal to the pylorus, the distal alimentary (Roux) limb, created by dividing the ileum 250 cm proximal to the ileocecal valve, is anastomosed end-to-end to the proximal duodenum. The biliopancreatic limb is anastomosed end-to-side to the distal ileum 100 cm proximal to the ileocecal valve, leaving a 100-cm common channel between the biliopancreatic and the distal alimentary limb.

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BPD. Short- and long-term weight loss and weight maintenance has been excellent. Loss of excess body weight has been 74 percent and 78 percent at 2 and 14 years, respectively. Other beneficial effects include significant improvement of the hypoventilation and obstructive sleep apnea syndromes, hypertension, venous stasis disease, hypercholesterolemia, glucose intolerance, and adult-onset diabetes mellitus following the procedure. Marceau and associates51 in Canada reported results in 465 patients undergoing BPD-DS. Mean percentage excess weight loss at 51 months follow-up was 73 percent, or an average of 101.2 pounds per patient. Only 4 percent of patients with diabetes mellitus, 42 percent with hypertension, and 49 percent with obstructive sleep apnea or hypoventilation syndromes still required medical treatment for these obesity-related conditions. When Marceau51 compared the 457 patients undergoing BPD-DS to 233 previous patients undergoing BPD, revision rates were lower and calcium and iron homeostasis improved in the BPD-DS group. However, there was no significant difference in weight loss between the two groups. Gagne and colleagues have reported a comparison between open and laparoscopic BPD-DS. In their report, 54 patients, 26 laparoscopic and 28 open procedures, were retrospectively reviewed. The laparoscopic approach had improved operative time, blood loss, and hospital stay; however, none reached statistical significance. Complication rates were slightly higher in the laparoscopic group (23 percent versus 17 percent), and death rate was higher in the laparoscopic group (7.6 percent versus 3.5 percent), but again, the levels did not reach statistical significance.54 Short-term complications from BPD vary, but include abdomical abscess (1.9 percent), anastomotic leak (1.9 percent), wound infection (5.6 percent), wound dehiscence (1.9 percent), respiratory failure (1.9 percent), and pancreatitis (1.9 percent). Late complications can include marginal ulceration (12 percent), bone demineralization (6 percent) secondary to calcium and vitamin D deficiencies, protein malnutrition (15.1 percent) characterized by hypoalbuminemia, anemia, edema, asthenia, and alopecia, and vitamin B12, iron, and folate deficiencies (5 percent).53 In summary, BPD with or without a duodenal switch has demonstrated superb weight-loss results. However, its complication rate is significant. There is a high rate of protein malnutrition, and the degree to which medications are malabsorbed is still unknown.

IV. LAPAROSCOPIC BARIATRIC SURGERY Since the first Roux-en-Y gastric bypass was described by Wittgrove et al. in 1994,55 laparoscopic bariatric surgery has been a rapidly evolving field. LAGB, verticalbanded gastroplasty, biliopancreatic diversion, and Roux-en-Y gastric bypass are technically challenging operations that require advanced laparoscopic surgery skills. Yet, the safety and feasibility of these procedures in the hands of qualified surgeons have been validated.32,56–62 LAGB is a less technically demanding procedure compared with other laparoscopic procedures, and it has gained widespread adoption outside the U.S.63,64 Most centers offer the laparoscopic approach for most uncomplicated candidates.

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V. CONCLUSION Obesity is a national health problem in the U.S. Thirty percent of the current American population is obese, compared with only 13 percent in 1960, placing a tremendous economic burden on the health-care system to care for the increased number of obesity-related health problems. An additional $30 billion is spent annually on medical weight-loss programs that use caloric restriction, exercise, or behavior modification and on appetite-suppressing medications. Though clouded in a history of less-than-successful attempts, surgery has finally emerged as the only effective long-term treatment for morbid obesity. Bariatric operations allow for substantial weight loss, extended weight maintenance, and control or reversal of obesity-related comorbidities. Several surgical options exist, each with their own pros and cons. Roux-en-Y gastric bypass is the gold standard. Lap-Band shows great promise. Biliopancreatic bypass is an effective operation for morbid obesity, however, long-term studies regarding nutritional and drug malabsorption are still lacking. The laparoscopic approach is now the access method of choice. There is currently a very active effort to develop less-invasive methods of achieving weight loss. There are devices currently under investigation that provide some restriction without a formal surgical procedure. There is also significant work looking into gastric pacing/stimulation to help induce satiety and provide for weight loss. Scientists are actively measuring hundreds of hormones, cytokines, and metabolites before and during weight loss induced by surgery to try to see if there are any profiles that might predict success or failure for any given procedure. In the end, continued success of bariatric surgery will rest on the continuing refinement of the procedures themselves and also on the ability to select patients based on current knowledge, as well as novel biochemical predictors to increase the success of each procedure and to tailor the treatment to the patient. Regardless of the algorithm for selection or the procedure itself, the success of any surgical approach to morbid obesity requires a multidisciplinary team of internists, nurses, dietitians, psychologists, and surgeons to select the best candidates for this approach, to operate, and to provide long-term follow-up.

REFERENCES 1. Flegal, KM, Carroll, MD, Ogden, CL, and Johnson, CL, Prevalence and trends in obesity among US adults, 1999-2000, JAMA, 288:1723–1727, 2002. 2. Kremen, AJ, Linner, JH, and Nelson, CH, An experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann. Surg., 140:439, 1954. 3. Kucamarski, RJ, Prevalence of overweight and weight gain in the United States, Am. J. Clin. Nutr. 55:495S, 1992. 4. Alverez-Cordero, R, Treatment of clinically severe obesity, a public health problem: Introduction, World J. Surg., 22:905, 1998. 5. National Institutes of Health Consensus Conference, Health implications of obesity, Ann. Intern. Med., 103:1073, 1985.

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6. Melissas, J, Chistodoulakis, M, Spyridakis, M, et al., Disorders associated with clinically severe obesity: Significant improvement after surgical weight reduction, South. Med. J., 91:1143, 1998. 7. Finkelstein, EA, Fiebelkorn, IC, and Wang, G, State-level estimates of annual medical expenditures attributable to obesity, Obes, Res., 12(1):18–24, 2004. 8. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults, WMJ, 97:20, 1998. 9. Metropolitan height and weight tables, Stat. Bull. Metrop. Life Found., 64:3, 1983. 10. National Institutes of Health Development Consensus Statement, Gastrointestinal surgery for severe obesity, Am. J. Clin. Nutr., 55:615S, 1992. 11. Eckel, RH and Krauss, RM, American Heart Association call to action: Obesity as a major risk factor for coronary heart disease, AHA Nutritional Committee, Circulation, 97:2099, 1998. 12. Manson, JE, Coldita, GA, and Stampfer, MJ, A prospective study of obesity and risk of coronary heart disease in women, N. Engl. J. Med., 322:882, 1990. 13. Hubert, HB, Feinteib, M, and McNamera, PN, Obesity as an independent risk factor for cardiovascular disease. A 26 year follow-up of participants in the Framingham heart study, Circulation, 67:968, 1983. 14. Williams, SR, Jones, E, Bell, W, et al., Body habitus and coronary artery disease in men. A review with reference to methods of body habitus assessment, Eur. Heart J., 18:376, 1997. 15. Peiser, J, Lavie, P, Ovnat, A, and Charuzi, I, Sleep apnea syndrome in the morbidly obese as an indication for weight reduction surgery, Ann. Surg., 100:112, 1984. 16. Trzebicky, R, Uber die grenzen der zulassigkeit-resection, Arch. f. Klin. Chir., 48:54, 1894. 17. Halverson, JD, Wise, L, Wazna, MF, and Ballinger, WF, Jejunoileal bypass for morbid obesity, Am. J. Med., 64:461, 1978. 18. Payne, JH and DeWind, LT, Surgical treatment of obesity, Am. J. Surg., 118:141, 1969. 19. Behrns, KE, Smith, CD, Kelly, KA, and Sarr, MG, Reoperative bariatric surgery: Lessons learned to improve patient selection and results, Ann. Surg., 218:646, 1993. 20. Mason, EE and Ito, C, Gastric bypass, Ann. Surg., 170:329, 1969. 21. Jordan, JH, Hocking, MP, Rout, WR, and Woodward, ER, Marginal ulcer following gastric bypass for morbid obesity, Am. Surg., 57:286, 1991. 22. Pories, WJ, Flickinger, EG, Mellheim, D, et al., The effectiveness of gastric bypass over gastric partition in morbid obesity, Ann. Surg., 194:389, 1982. 23. Mason, EE, Printen, KJ, Blommers, TJ, et al., Gastric bypass in morbid obesity, Am. J. Clin. Nutr., 33:395, 1980. 24. Printen, KJ and Mason, EE, Gastric surgery for relief of morbid obesity, Arch. Surg., 106:428, 1973. 25. Mason, EE, Vertical banded gastroplasty for obesity, Arch. Surg., 117:701, 1982. 26. Scopinaro, N, Gianetta, E, Civalleri, D, et al., Partial and total biliopancreatic bypass in the surgical treatment of obesity, Int. J. Obes., 5:421, 1981. 27. Marceau, P, Hould, FS, Simard, S, et al., Biliopancreatic diversion with duodenal switch, World J. Surg., 22:947, 1998. 28. Bo, O and Modalshi, O, Gastric banding, a surgical method of treating morbid obesity: preliminary report, Int. J. Obes., 7:493, 1983. 29. Kuzmak, LI, Stoma adjustable silicone gastric banding, Probl. Gen. Surg., 9:298, 1992. 30. Chelala, E, Cadiere, GB, Favretti, F, et al., Conversions and complications in 185 laparoscopic adjustable silicone gastric banding cases, Surg. Endosc., 11:268, 1997.

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31. Belachew, M, Legrand, M, Vincent, V, et al., Laparoscopic adjustable gastric banding, J. Surg., 22:955, 1998. 32. Wittgrove, AC and Clark GW, Laparoscopic gastric bypass, Roux-en-Y: Technique and results in 300 patients with 3-34 months follow-up, Scientific presentation, 6th World Congress of Endoscopic Surgery, Rome, Italy, June 3–6, 1998. 33. Lonroth, H, Dalenback, J, Haglind, E, and Lundell, L, Laparoscopic gastric bypass. Another option in bariatric surgery, Surg. Endosc., 10:636, 1996. 34. Goergen, M, Ansay, J, Azagra, JS, et al., Mason’s vertical banded gastroplasty for morbid obesity. Results of a randomized prospective trial of laparoscopic vs. open approach, Surg. Endosc., 12:601, 1998. 35. Ren, CJ and Fielding, GA, Laparoscopic adjustable gastric banding: surgical technique, J. Laparoendosc. Adv. Surg. Tech. A., 13(4):257–63, 2003. 36. Fox, SR, Fox, KM, Srikanth, MS, and Rumbaut R, The Lap-Band system in a North American population, Obes. Surg., 13(2):275–80, 2003. 37. Ren, CJ, Horgan, S, and Ponce, J, US experience with the LAP-BAND system, Am. J. Surg. 184(6B):46S–50S, 2002. 38. Rubenstein, RB, Laparoscopic adjustable gastric banding at a U.S. center with up to 3-year follow-up, Obes. Surg., 12(3):380–4, 2002. 39. O’Brien, PE and Dixon, JB, Lap-band: outcomes and results J. Laparoendosc. Adv. Surg. Tech. A., 13(4):265–70, 2003. 40. O’Brien, PE, Dixon, JB, Brown, W, Schachter, LM, Chapman, L, Burn, AJ, Dixon, ME, Scheinkestel, C, Halket, C, Sutherland, LJ, Korin, A, and Baquie, P, The laparoscopic adjustable gastric band (Lap-Band): a prospective study of medium-term effects on weight, health and quality of life, Obes. Surg., 12(5):652–60, 2002. 41. Fielding, GA, Rhodes, M, and Nathanson, LK, Laparoscopic gastric banding for morbid obesity. Surgical outcome in 335 cases, Surg. Endosc., 13(6):550–4, 1999. 42. Ren, CJ, Weiner, M, and Allen, JW, Favorable early results of gastric banding for morbid obesity: the American experience, Surg. Endosc., 18(3):543–546, 2004. 43. Pories,WJ, Swanson, MS, MacDonald, KG, et al., Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus, Ann. Surg, 222:339, 1995. 44. Cowan, GS and Buffington, CK, Significant changes in blood pressure, glucose, and lipids with gastric bypass, World J. Surg., 22:987, 1998. 45. Pope, GD, Birkmeyer, JD, and Finlayson, SR, National trends in utilization and inhospital outcomes of bariatric surgery, J. Gastrointest. Surg., 6(6):855–60; discussion 861, 2002. 46. Sagar, PM, Surgical treatment of morbid obesity, Br. J. Surg., 82:732, 1995. 47. Griffen, WO, Jr., Young, L, and Stevenson, CC, A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity, Ann. Surg., 186:500, 1977. 48. Kellum, JM, DeMaria, EJ, and Sugarman, HJ, The surgical treatment of morbid obesity, Curr. Probl. Surg., 35:791, 1998. 49. Printen, KJ, Scott, D, and Mason, EE, Stomal ulcers after gastric bypass, Arch. Surg., 115:525, 1980. 50. Mason, EE, Tang, S, Renquist, KE, et al., for the National Bariatric Surgery Registry Contributors: A decade of change in obesity surgery, Obes. Surg., 7:189, 1997. 51. Marceau, P, Hould, FS, Simard, S, et al., Biliopancreatic diversion with duodenal switch, World J. Surg, 22:947, 1998. 52. Hess, DS and Hess, DW, Biliopancreatic diversion with a duodenal switch, Obes. Surg., 6:122, 1996.

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53. Scopinaro, N, Adami, GF, Marinari, GM, et al., Biliopancreatic diversion, World J. Surg., 22:936, 1998. 54. Won-Woo, K, Gagner, M, Kini, S, Inabet, WB, Quinn, T, Herron, D, and Pomp, A, Laparoscopic vs. open biliopancreatic diversion with duodenal switch: a comparative study, J. G.I. Surg., 7:552–557, 2003. 55. Wittgrove, AC, Clark, GW, and Tremblay, LJ, Laparoscopic gastric bypass, Rouxen-Y: preliminary report of five cases, Obes. Surg., 1994; 4:353–357. 56. Cadiere, GB, Bruyns, J, Himpens, J, and Favretti, F, Laparoscopic gastroplasty for morbid obesity, Br. J. Surg., 81:1524, 1994. 57. Chua, TY and Mendiola, RM, Laparoscopic vertical banded gastroplasty: The Milwaukee experience, Obes. Surg., 5:77, 1995. 58. Deitel, M, Laparoscopic bariatric surgery, Surg. Endosc., 11:965, 1997. 59. Gagner, M, Garcia-Ruiz, A, Arca, M, and Heniford, BT, Laparoscopic isolated gastric bypass for morbid obesity, Surg. Endosc, 13:S6, 1999. 60. Hallerback, B, Glise, H, Johansson, B, and Johnson, E, Laparoscopic surgery for morbid obesity, Eur. J. Surg., 582:128, 1998. 61. Lonroth, H and Dalenback, J, Other laparoscopic bariatric procedures, World J. Surg., 22:964, 1998. 62. Schauer, PR, Ikramuddin, S, Gourash, W, and Panzak, G, Laparoscopic Roux-en-Y gastric bypass for super-morbid obesity, Surg. Endosc., 13:A75, 1999. 63. Fried, M, Peskova, M, and Kasalicky, M, The role of laparoscopy in the treatment of morbid obesity, Obes. Surg., 8:520, 1998. 64. Garfinkel, L, Overweight and cancer, Ann. Intern. Med., 103:1034, 1985.

8

Postoperative Management of the Bariatric-Surgery Patient Jarol Boan, M.D., M.P.H.

CONTENTS I. Introduction................................................................................................125 II. Surgical Procedures ...................................................................................125 A. Roux-en-Y Gastric Bypass................................................................125 B. Lap-Band ...........................................................................................126 III. Predictors of Complications ......................................................................126 A. Phase One Complications (One to Six Weeks) ................................127 B. Phase Two Complications (Six Weeks to Two Months) ..................128 C. Phase Three Complications (2 to 12 Months)..................................130 IV. Summary ....................................................................................................132 References..............................................................................................................132

I. INTRODUCTION The prevalence of morbid obesity is increasing considerably in the U.S., and the number of bariatric procedures for weight loss has grown dramatically over the last five years. The American Society for Bariatric Surgery reported that more than 140,000 gastrointestinal surgeries for obesity were performed in 2004,1 and the numbers are increasing dramatically as more surgeons become proficient at the procedure. After the surgical follow-up care is completed, primary-care physicians interact with these patients for a multitude of medical problems. This review outlines the common problems encountered in the postoperative management of the bariatricsurgery patient.

II. SURGICAL PROCEDURES A. ROUX-EN-Y GASTRIC BYPASS Roux-en-Y gastric bypass (RYGB) is considered the gold standard for achieving a sustainable weight loss in the morbidly obese. 2 This procedure purports an average 125

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weight loss of 100 lbs after one year and has low mortality and morbidity rates for patients.3 The 30 day mortality rate is reported to be 0.5 percent–1.9 percent.4,5 The most common causes of death are pulmonary embolus, gastrojejunal anastomotic leak, respiratory failure, sepsis, and GI hemorrhage. These patients are high-risk surgical patients with multiple underlying comorbidities, and 50 percent of deaths are due to underlying comorbidities (hypertension, diabetes, sleep apnea, pulmonary embolus, cirrhosis, etc.).6 With the introduction of a laparoscopic technique for RYGB, risks associated with this surgery decreased dramatically. In a recent series of surgeries comparing open gastric bypass to laparoscopic technique, laparoscopic RYGB was associated with decreased operative mortality, wound infection, and incisional hernia.4 Unfortunately, laparoscopic gastric bypass has been associated with an increased incidence of stomal stenosis and internal hernia.7

B. LAP-BAND Lap-Band adjustable gastric-banding device was Food and Drug Administration approved in 2001.8 The Lap-Band is a silastic ring that forms a small gastric pouch and can be removed when weight loss has been achieved. The procedure is less invasive than the RYGB and has a lower postoperative mortality rate. Unfortunately, the morbidity rate is higher, and the degree of weight loss is less than that with the RYGB. In a review of 500 cases,9 10.4 percent of patients had complications requiring an abdominal reoperation. In another study, five-year follow up of patients with Lap-Band showed 10 percent of patients had the band removed and 2.4 percent were converted to a RYGB.10 The FDA has tracked complaints for this procedure. Between June 2001 and August 2002 there were 556 complaints. The majority of these were related to device malfunction, most commonly leak at the access port. In this series, only two deaths related to the procedure were reported.11 Despite its complication rate, it is a very popular procedure due to its ease of insertion and its ability to achieve weight loss.

III. PREDICTORS OF COMPLICATIONS In an analysis of the complication rate after bariatric surgery, Schwartz et al. analyzed 600 laparoscopic RYGBs and found the overall complication rate approached 26 percent.12 One of the main predictors of complications is the experience of the surgeon.13 In fact, the American Society of Bariatric Surgeons recommends that a surgeon perform 100 procedures before technical expertise is obtained. The higher the weight (body-mass index > 55 kg/m2), the more likely there will be complications. Males over 50 years of age are at increased risk of complications. The presence of hypertension and sleep apnea will increase the likelihood of complications. Interestingly, the presence of diabetes is not a predictor of complications. The presence of psychiatric illness is believed to be a predictor of complications. The data supporting this conclusion is discordant. In some series, severe psychiatric illness is associated with poor outcome, such as inadequate weight loss, chronic

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TABLE 8.1 Post-Operative Complications After Major Complications

Minor Complications

Peritonitis/leak Pulmonary embolus Respiratory failure Wound dehiscence Small bowel obstruction Cardiac arrest Intra-abdominal

Pulmonary atelectasis Wound infection Urinary tract infection Stomal stricture Marginal ulcer Hypotension

nausea and vomiting, poor compliance, and weight regain. On the other hand, weight loss after bariatric surgery is associated with an improvement in depression, selfesteem, and productivity. In some cases, patients who have a history of emotional eating combined with poor psychological insight are more likely to develop somatization. These patients are likely to have repeat visits to the physician for a variety of complaints. Screening tools for predicting which patients will have an unsatisfactory outcome after bariatric surgery are needed.

A. PHASE ONE COMPLICATIONS (ONE

TO

SIX WEEKS)

Complications following surgery are often managed by the surgeons involved. As shown in Table 8.1, postoperative complications include postoperative bleeding, staple-line leak, bowel perforation, bowel obstruction, severe wound infections, minor wound infections, pulmonary embolism, perioperative myocardial infarction (MI), pneumonia, and urinary-tract infection. The most disastrous complication associated with RYGB, a staple-line leak at the gastrojejunal anastomosis, has a reported incidence of 4.6%.7 Table 8.2 lists its clinical features. In approximately one-third of leaks, the patient requires reexploration and is taken back to the operating room. Every patient should be aware of the potential of this serious complication prior to undergoing bariatric surgery.

TABLE 8.2 Post-Operative Anastomotic Leak Reported rate Mean time to presentation Symptoms Treatment Prognosis

4.6% Within 1–2 days post-op Tachycardia, respiratory distress NPO, drainage tube, watch carefully Can progress to systemic sepsis and organ failure

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During the immediate perioperative period, obesity-related medical comorbidities change dramatically. Blood pressure often decreases to the normal range without medications, and blood-pressure monitoring is important to document during all postoperative visits. Hypotension is commonly seen, especially if there is poor fluid intake or persistent postoperative vomiting. The need for reinstituting antihypertensive medications needs to be monitored carefully. Routine antireflux medications should be discontinued, unless symptoms persist after surgery. Every patient with a diagnosis of diabetes should have frequent monitoring of blood glucose, and a sliding scale for subcutaneous insulin injections should be provided. Many diabetic patients decrease the need for insulin after bariatric surgery. In diabetic patients previously managed with oral medications, such as sulfonylureas or thiazolidinediones, there is an increased risk of hypoglycemia after bariatric surgery. The biguanides (metformin) is the safest drug in the postoperative period since it is not associated with dramatic fluctuations in blood glucose. The decreased requirement for insulin and modification of oral medications after bariatric surgery is due to several reasons. The average caloric intake ranges between 400–800 Kcal/day for the first month and is associated with rapid weight loss, and decreased insulin needs. Weight loss can be significant in the first month postoperatively, ranging from 20–40 lbs, resulting in decreased need for insulin. It has also been suggested that the anatomical changes after RYGB results in changes in insulin signaling. Discontinuation of diabetic medications should be entertained when blood glucose normalizes and after the patient is eating. Patients on antidepressants and other psychiatric medications should have these medications continued in the immediate postoperative period. Dramatic weight loss occurs in the first few months after bariatric surgery, and this can be associated with emotional liability. Emotional stability associated with continuation of antidepressants allows smooth transition after surgery, and patients should be urged to continue these medications Patients in this phase are dealing with many different changes, both physiological and psychological. The small gastric pouch only allows very small portion sizes, and they feel full and satisfied. They are not hungry, and often forget to eat. Attempts at overeating result in vomiting, and they quickly learn to control portion sizes and food reactions. The patient in this phase is dealing with significant changes in comorbidities, physiological feedback, and psychological changes associated with surgery.

B. PHASE TWO COMPLICATIONS (SIX WEEKS

TO

TWO MONTHS)

In addition to the medical monitoring of the comorbidities listed above, the postoperative care of the bariatric-surgery patient requires additional components in phase two. This phase is characterized by a distinct set of complications as the patient struggles to learn new ways of eating and becomes skilled at interpreting physiological feedback. Psychological characteristics become a predominant factor in the postoperative visits, often characterized by food and weight obsessions. The most common complication in this phase after bariatric surgery is prolonged vomiting. A diet history recording dietary intake and portion sizes is important. After

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TABLE 8.3 Stomal Stenosis/Stricture Reported rate Mean time to presentation Symptoms Treatment

2.8–7.0% 6–7 weeks Nausea, vomiting, early satiety, food intolerances, abdominal pain Endoscopic balloon dilatation, repeat dilatation required in 17% of cases

dietary indiscretions and vomiting associated with bulimia are ruled out, a stomal stricture at the gastrojejunal anastomosis should be considered. The reported prevalence of stricture ranges from 2.8 percent–7 percent.14,15 The presenting complaint is vomiting and postprandial pain in the gastric pouch (Table 8.3). A barium swallow often detects narrowing at the gastrojejunal anastomosis, and a referral to a gastroenterologist for endoscopic dilatation should be made. Marginal ulcers at the anastomosis should be searched for. A decision to insert a nasojejunal feeding tube at the time of endoscopy should be considered depending on the degree and rate of weight loss. Dumping syndrome occurs in approximately 50 percent of patients after RYGB. The same phenomenon does not appear to happen after the Lap-Band procedure. It is characterized by symptoms of nausea, shaking, diaphoresis, and diarrhea immediately after eating high-glucose containing foods. It is considered a positive outcome after RYGB, especially in sweet eaters, since it results in food aversion to sweet eating. Patients who experience these symptoms should be advised to avoid the foods that produce them. After gastric-bypass surgery, there are psychological changes associated with the change in eating patterns, and these changes can cause significant dysfunction. It is well-established that extreme weight loss results in symptoms of psychopathology. In the classic Keys’ studies in the 1950s, weight loss of 25 percent resulted in the development of lethargy, depression, and other psychopathology.16 Preoperatively, patients with morbid obesity often use food for emotional reasons, and when they experience a small gastric pouch postoperatively, they often grieve the loss of food. Displaced emotions often result in somatization with symptoms of nausea and vomiting. It is important that physicians recognize the psychological aspect of the loss of food after gastric-bypass surgery, and reassure patients that the symptoms are related to the small gastric-pouch size. Antidepressants often help to decrease the anxiety related to the grieving associated with the loss of food, although the use of antidepressants needs to be approached with an empathetic style. Nutritional deficiencies are common after bariatric surgery for two reasons: inadequate dietary intake and the surgical procedure itself. The lack of intrinsic factor results in inability to absorb vitamin B12. Intramuscular injections of 1000 μg of Vitamin B12 should be given every six months for life. Long-term nutritional deficiencies are common, especially if dietary variety is lacking and vitamin supplements are not ingested regularly. After RYGB, the lack of acid in the gastric pouch results in poor absorption of iron, and iron deficiency has been described in

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up to 15 percent of patients. It is important to emphasize the importance of a daily multivitamin, in addition to adequate intake of dietary fruits and vegetables, in order to prevent nutritional deficiencies. Clearly, a significant number of individuals go into obesity surgery with preexisting eating-disordered behavior. To maintain the weight loss that typically follows surgery, they have to change their eating patterns dramatically. General normalization of eating behavior has been reported characterized by fewer meals, less food consumed at each meal, less eating between meals, and less eating in response to strong emotions.17,19 Severe binge eating becomes virtually impossible following gastric bypass due to the severely restricted stomach. Despite this, patients with a preexisting eating disorder continue to have disordered-eating patterns.

C. PHASE THREE COMPLICATIONS (2

TO

12 MONTHS)

In the majority of patients after bariatric surgery, this phase is characterized by a significant change in eating habits, improvement in medical comorbidities, and continued weight loss. The most important change in eating habits that result from bariatric surgery is the change in portion size. Initially, the stomach can only tolerate 30 cc at one time, but over time there is a gradual increase in portion size. There are very few reports of the actual change in stomach size. At three months, patients are ingesting an average of 1500 Kcal per day in three to six meals per day. It is important in this stage to emphasize normal eating patterns and prevent development of a grazing lifestyle. With appropriate nutrition advice, patients decrease the need for frequent meals and increase the amount eaten at each meal, reaching three meals a day by six months. Patients learn to be satisfied with very small portion sizes and maintain a dietary intake appropriate for their new size by the 12th month followup visit. For a minority of patients, this phase is characterized by difficulty in adjustment to weight loss, food intolerances, self-destructive behaviors, and, occasionally, requests for a reversal of the procedure. These patients tend to be time-consuming for the treating physician. Discerning the difference between psychological symptoms and physical symptoms can be difficult in this phase. Gallstone formation is associated with rapid weight loss,20 and the reported prevalence of gallstones at six months postoperatively is 22 percent.21 Small-bowel obstruction from internal hernias after laparoscopic surgery13 can present with crampy abdominal pain, nausea, and vomiting (Table 8.4). A high index of suspicion and close consultation with the bariatric surgeon is needed. Common food intolerances associated with bariatric surgery include bread, rice, pasta, and meat. Vomiting often occurs after eating these foods, resulting in food aversions. For patients who enjoyed these foods prior to the surgery, the loss of food variety results in anger and frustration. These patients will often complain that they experience anxiety and fear when eating. They often express buyer’s remorse, may request extensive investigations for problems with the gastric pouch, and request referral to another surgeon for a reversal of the procedure. Reassurance about the ability of the pouch to tolerate a wide variety of foods with time is necessary. Often, fresh fruits and vegetables are tolerated without a problem, resulting in a significant

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TABLE 8.4 Small Bowel Obstruction Reported rate Time to presentation Symptoms Diagnosis Common causes Treatment

1.5–7.3% Early (within 1 week) Late (several months later) Crampy abdominal pain, nausea, vomiting High index of suspicion Radiological studies can be normal Internal hernia, torsion of Roux limb at transverse mesocolon, adhesions, jejunal-jejunal intussusception Laproscopic or open exploration often required

change in eating habits compared to preoperative eating habits. Some patients have continuing food intolerances, especially to red meat, and become vegetarian. Reassurance and empathy is essential to help the patient overcome food intolerances. By six months, most patients are able to tolerate most foods, and tend to eat three small meals per day. If problems continue, referral to an experienced dietitian can be helpful. Patients with a preoperative history of eating disorders (binge eating, reactive overeating, etc.) tend to manifest difficulty in adjusting to the change in eating habits more commonly. Referral to an experienced psychologist can help unmask some of the underlying emotional issues associated with food. Weight loss is rapid in the first six months, averaging 10–15 lbs per month. Average weight loss at the six-month follow-up visit is 60–80 lbs. Thereafter, the rate of weight loss tends to slow down to 5–7 lbs per month, reaching a peak at 12 months postoperatively, averaging 100–120 lbs. Despite its superiority to other methods of weight loss for the morbidly obese, surgery still carries the risk of failed weight loss or weight regain. When there is weight regain, it typically begins 18–24 months postsurgery.22–24 Delin and Watts report that although most patients do well initially, some ultimately fail to sustain their improvement.23 Continuous snacking and consuming large quantities of soft or liquid foods has been described. Some researchers attribute the weight gain to physiological factors, but others claim that inadequate coping strategies are usually at the source of patients’ inability to maintain weight loss.25 Unfortunately, a small percentage of patients become grazers after bariatric surgery and have a poor weight loss. Rapid weight loss results in many psychological changes as the body shape changes. Several studies have shown increases in self-esteem, self-confidence, assertiveness, and expressiveness.26,27 Improvements in the patients’ self-esteem and psychological state result in greater assertiveness and improvement in social interaction, sexual activity, and work performance. On the other hand, a significant number of patients discover they have underdeveloped coping mechanisms in their new persona as a thin person. These patients often require psychological therapy to deal with issues of past sexual abuse, bodyimage changes, and relationships with intimate partners.

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The most striking changes in medical symptoms after bariatric surgery are those that are most difficult to quantify. Fatigue improves with an increase in energy level. Exercise habits improve with an increase in activity of daily living, as well as recreational activity. In a majority of patients, back pain disappears. Osteoarthritis improves to a lesser degree, and is dependent on the degree of underlying bone and cartilage damage. The advantage of bariatric surgery is that the preoperative risk for an orthopedic procedure decreases, making subsequent surgery risks similar to those of lean controls. Sleep apnea tends to improve significantly, and refitting of the mask is often needed by six months postoperatively. At 12 months postop, repeat overnight somnography is suggested to document the need for continued CPAP. While weight loss improves the social lives of patients, they often have difficulty adjusting to dramatic changes in social circles. Patients previously involved in relationships with other obese persons may find that changes in their lifestyle (i.e., more activity, greater social contacts, and changes in eating behavior) become incompatible with that of presurgical relationships. Given that the capacity of the stomach is significantly reduced following restrictive surgery, social and business functions that revolve around food become awkward. Family members, friends, coworkers, and acquaintances may also react with envy or feel threatened following the patient’s rapid weight loss. The patient may feel resentment at his sudden social acceptance following weight loss. Being related to positively by people who once treated you badly because of your weight may not be a joyful experience.23 These issues are often dealt with in long-term support groups. When weight loss has stabilized, usually at the 12-month follow-up visit, the majority of patients request information about plastic surgery. Unfortunately, most insurance companies regard plastic surgery following bariatric surgery as cosmetic surgery and will not cover it. There are cases where the abdominal pannus is infected or excoriated, and documentation will be required by the insurance company for coverage. An experienced plastic surgeon will be helpful for those who wish to pursue plastic surgery.

IV. SUMMARY Morbid obesity is a complex disease with a multitude of associated diseases that require special management after bariatric surgery. The patient with a BMI > 40 kg/m2 is a unique patient. It is necessary to modify many of the standard medicalassessment techniques, and recognize the unique interaction of psychosocial issues and medical issues when caring for a patient after bariatric surgery.

REFERENCES 1. Steinbrook, R, Surgery for severe obesity, N. Engl. J. Med., 350(11):1075–9, 2004. 2. Pories, WJ, MacDonald, KG, Morgan, EJ, Sinha, MK, Dohm, GL, Swanson, MS, Barakat, HA, Khazanie, PG, Leggett-Frazier, N, Long, SD, O’Brien, KF, and Caro, JF, Surgical treatment of obesity and its effect on diabetes: 10-y follow-up, Am. J. Clin. Nutr., 55:582S–585S, 1992.

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3. DeMaria, EJ, Sugerman, HJ, Kellum, JM, et al., Results of 281 consecutive total laparoscopic Roux-en-Y gastric bypasses with a linear stapled gastrojejunostomy to treat morbid obesity, Ann. Surg., 235:640–645, 2002. 4. Podnos, YD, Jimenez, JC, Wilson, SE, Stevens, CM, and Nguyen, NT, Complications after laparoscopic gastric bypass: a review of 3464 cases, Arch. Surg., 138(9):957–61, 2003. 5. Flum DR, Dellinger EP, Impact of gastric bypass operation on survival: a population based analysis. J. Am. Coll. Surg., 199:543–551, 2004. 6. Melinek, J, Livingston, E, Cortinia, G, and Fishbein, MC, Autopsy findings following gastric bypass surgery for morbid obesity, Arch. Path. Lab. Med., 126(9):1091–1095, 2002. 7. Maggard MA, Shurgarman LR, Suttorp M, et al. Meta-Analysis: surgical treatment of obesity, Ann. Int. Med., 142:547–559, 2005. 8. Lap-Band, Adjustable gastric band system report of safety and effectiveness data, U.S. Federal Drug Agency Center for Devices and Radiological Health NDA, 2001, available at www.fda.gov/cdrh/pdf/P000008b.pdf. 9. Zinzindohoue, F, Chevallier, JM, Douard, R, Elian, N, Ferraz, JM, Blanche, JP, Berta, JL, Altman, JJ, Safran, D, and Cugnenc, PH, Laparoscopic gastric banding: a minimally invasive surgical treatment for morbid obesity: prospective study of 500 consecutive patients, Ann. Surg., 237(1):1–9, 2003. 10. Angrisani, Obes. Surg., 13, Abstr. 13, 2003. 11. Brown, SL, Obes. Surg., 13, Abstr. 14, 2003. 12. Schwartz, ML, Drew, RL, and Chazin-Caldie, M, Laparoscopic Roux-en-Y gastric bypass: preoperative determinants of prolonged operative times, conversion to open gastric bypasses, and postoperative complications, Obes. Surg., 13(5):734–738, 2003. 13. Perugini, RA, Mason, R, Czerniach, DR, Novitsky, YW, Baker, S, Litwin, DE, and Kelly, JJ, Predictors of complication and suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass: a series of 188 patients, Arch. Surg., 138(5):541–545, 2003. 14. Suter, M, Giusti, V, Heraief, E, Zysset, F, and Calmes, JM, Laparoscopic Roux-enY gastric Bypass: initial 2-year experience, Surg. Endoscop., 17(4):603–609, 2003. 15. Nguyen, NT, Stevens, CM, and Wolfe, BM, Incidence and outcome of anastomotic stricture after laparoscopic gastric bypass, J. Gastroint. Surg., 7(8):997–1003, 2003. 16. Keys, A, The Biology of Human Starvation, Minneapolis, University of Minnesota Press, 1950. 17. Mills, MJ and Stunkard, AJ, Behavioral changes following surgery for obesity, Am. J. Psychiatr., 2:239–243, 1976. 18. Crisp, AJ, Kalucy, RS, and Pilkington, TR, Some psychological consequences of ileojejunal bypass surgery, Am. J. Clin. Nutr., 30:109–120, 1977. 19. Adami, GF, Meneghelli, A, and Scopinaro, N, Night eating and binge eating in obese patients, Int. J. Eat. Disord., 25:335–338, 1999. 20. Weinsier, RL, Wilson, LJ, and Lee, J, Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation, Am. J. Med., 98(2):115–7, 1995. 21. Villegas L, Schneider, B, Provost, D, Chang, C, Scott, D, Sims, T, Hill, L, Hynan, L, and Jones, D, Is routine cholecystectomy required during laparoscopic gastric bypass? Obes. Surg., 14(1):60–6, 2004. 22. Shamblin, JR and Shamblin, WR, Bariatric surgery should be more widely accepted, S. Med. J., 80:861–865, 1987.

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23. Hsu, LK, Benotti, PN, Roberts, SB, Saltzman, E, Shikory, S, Rolls, BJ, and Rand, W, Nonsurgical factors that influence the outcome of bariatric surgery: a review, Psychosom. Med., 60:338–346, 1998. 24. Powers, PS, Rosemurgy, A, Boyd, F, and Perez, A, Outcome of gastric restriction procedures: weight, psychiatric diagnoses, and satisfaction, Obes. Surg., 7:471–477, 1997. 25. Delin, CR and Watts, J, Success in surgical intervention for morbid obesity: is weight loss enough? Obes. Surg., 5:189–191, 1995. 26. Leon, GR, Eckert, ED, Teed, DB, and Buchwald, H, Changes in body image and other psychological factors after intestinal bypass surgery for massive obesity, J. Behav. Med., 2:39–55, 1979. 27. Solow, C, Silberfarb, P, and Swift, K, Psychosocial effects of intestinal bypass surgery for severe obesity, N. Engl. J. Med., 290:300–304, 1974.

Section II Pathophysiology and Treatment of Diabetes

Introduction As pointed out in section I, there is a very strong link between obesity and bloodglucose dysregulation, which is apparent in type 2 diabetes. The growing incidence of obesity among children and adults, in the U.S in particular, is accompanied by a commensurate increase in the prevalence type 2 diabetes in all individuals. As expected, with the various comorbidities associated with diabetes, there is also a concomitant increase in the incidence of diabetic complications. Consequently, there is an exponential rise in the health-care costs associated with the management of diabetes and its many complications. In this section, therefore, there is an appropriate overview of the rising incidence of type 2 diabetes and its various complications in many populations of the world. There is also detailed review of how the high-energy nutrient, fat, which is abundant in obesity, inhibits the utilization of carbohydrates, leading to impaired bloodglucose regulation. The interaction of nutrients and the effects on blood-glucose levels is then illustrated with extensive discussions on both the pathophysiology and treatment of type 2 diabetes in both children and adults. Furthermore, owing to the disproportionate incidence of type 2 diabetes in underrepresented ethnic minorities in the U.S, there is a special review that is focused on the issues involved in the diagnosis and treatment of diabetes in these populations. As pointed out earlier, there is a universal increase in the incidence of type 2 diabetes and its many complications. Therefore, it becomes an issue of particular concern for the Third World countries with little or no resources to address these problems. In one chapter, first, there is an adequate overview of the etiology of diabetes in developing countries, and the effect of many different factors, including culture and economic status, on the prevalence and treatment of diabetes among these populations. Second, there is a good outline of what it is going to take to avoid the looming calamity that would be the toll of diabetes and its complications in developing countries. Diabetes in pregnancy presents a particular challenge to the physician. With the rising incidence of diabetes, it is, therefore, most appropriate that a detailed overview of the strategies to manage the different forms of diabetes in pregnancy is provided in this section. The section ends with a Web-based education program for the management of diabetes, as illustrated with type 1 diabetes.

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Epidemiology, Risks, and Health-Care Expenditures for Diabetes and Its Complications William F. Kendall, Jr., M.D.

CONTENTS I . Estimated Health-Care Expenditures Associated with Diabetes ..............140 II. Prevalence of Diabetes ..............................................................................140 III. Defining Impaired Glucose Tolerance, Insulin Resistance, and Diabetes Mellitus ................................................................................142 IV. Diagnostic Criteria for Diabetes Mellitus .................................................143 V. Risk Factors ...............................................................................................145 A. Gestational Diabetes..........................................................................145 B. Posttransplantation Diabetes .............................................................145 C. Association of Obesity with Diabetes ..............................................146 D. Diet and Diabetes ..............................................................................147 E. Diabetes and Microalbuminuria........................................................147 F. Effects of Alcohol and Cigarettes .....................................................147 G. Diabetes and Physical Limitations....................................................148 H. Diabetes and Mental Health..............................................................148 VI. Diabetic Complications .............................................................................149 A. Coronary-Vascular Disease ...............................................................149 B. Peripheral Neuropathy and Peripheral Vascular Disease .................150 C. Cerebrovascular Disease ...................................................................151 D. Erectile Dysfunction..........................................................................152 E. Diabetic Nephropathy .......................................................................152 F. Retinopathy........................................................................................152 G. Dental Disease...................................................................................153 VII. Mortality ....................................................................................................153 VIII. Level of Health Care .................................................................................153 References..............................................................................................................154

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I. ESTIMATED HEALTH-CARE EXPENDITURES ASSOCIATED WITH DIABETES Diabetes mellitus has been present since antiquity. It was described in 400 B.C. as a disease of “well-fed people,” and Bose wrote in 1895 “amongst the Zemindars and Talookdars, who consider it a pride and honor to lead an indolent life, diabetes is a common disorder” (1). It is a common disease that is now estimated to affect more than 16 million Americans and more than 100 million people worldwide (2, 3). It is most prevalent in countries such as India, China, and the U.S. (4). Its direct and indirect costs account for at least 15 percent of health-care expenditure in the U.S., which totals at least $100 billion annually (2, 5, 6). The annual estimated cost in other countries is just as formidable. The estimated annual health-care costs associated with diabetes in various developed countries in 1995 (4) are shown in Table 9.1. A large portion of the costs of diabetes is associated with its complications (7). The University Group Diabetes Program, the earliest randomized clinical trial of the treatment of hyperglycemia in people with diabetes, failed to show a positive effect of glycemic control on the prevention of the development or progression of microvascular complications (8). However, the Diabetes Control and Complication Trial and the United Kingdom Prospective Diabetes Study clearly showed that strict control of blood glucose could positively affect the progression of diabetic complications (9). It has also been shown that elevated hemoglobin A1c (HbA1c), an indicator of poor glucose control, is associated with increased mortality in diabetic populations (9). The American Diabetes Association recommends a goal for HbA1c of < 7 percent, with the need for intervention when HbA1c is > 8 percent (10).

II. PREVALENCE OF DIABETES Type 1 diabetes mellitus comprises approximately 10 percent of diabetes incidence (11). Most cases of type 1 diabetes mellitus are sporadic, with only 10 percent to 15 percent of affected individuals having a first-degree relative with type 1 diabetes mellitus at the time of diagnosis (11). The risk of developing diabetes is 5 percent if a family member also has type 1 diabetes mellitus, in comparison to general population risk of 0.2 percent (11). Type 1 diabetes mellitus is characterized by Tlymphocyte mediated destruction of insulin-producing cells of the pancreatic islets of Langerhans (11). A majority of cases of type 1 diabetes mellitus result from proven beta-cell destruction and are classified as type 1a. Ten percent to 20 percent of cases are antibody negative and are classified as idiopathic (11). Type 2 diabetes mellitus comprises approximately 90 percent of diabetes (11). Prevalence among ethnic groups in the U.S. include: 2 percent to 8 percent Caucasians; 4 percent to 12 percent African Americans; 4 percent to 19 percent Mexican Americans; 14 percent to 12 percent Asian Americans; and 35 percent to 50 percent Pima Native Americans, with Arizona having the highest diabetes incidence in the world among this group (Table 9.2) (11). In comparison, a Singapore national survey showed a prevalence of 13.1 percent among Mauritian Chinese, 2.7 percent in Asian Indians in Asia, and 1.6 percent in Chinese in China (12). It is estimated that diabetes

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TABLE 9.1 The Estimated Annual Health-Care Costs Associated with Diabetes in Various Developed Countries, in 1995 Country Cost

Denmark $247 billion

Germany $145 billion

Japan $18.7 billion

United Kingdom $10.8 billion

Italy $3.78 billion

Sweden $2.0 billion

Spain $1.78 billion

Source: King, H, Aubert, RE, and Herman, WH, Diabet. Care, 21(9):1414–1431, 1998.

TABLE 9.2 Estimated Prevalence of Diabetes Mellitus Among Ethnic Groups in the U.S. Caucasians

African Americans

Mexican Americans

Asian Americans

Pima Native Americans

2%–8%

4%–12%

4%–19%

4%–12%

35%–50%

is undiagnosed in one-third of all people with diabetes (13). The lifetime risk of developing diabetes mellitus is 40 percent if there is one parent with type 2 diabetes mellitus, 80 percent to 100 percent if there are two affected parents, 35 percent if there is an affected sibling, and 70 percent to 80 percent among monozygotic twins (11). Only 5 percent to 10 percent of type 2 diabetes mellitus cases are due to slowly progressive beta-cell dysfunction (11). Approximately 10 percent to 15 percent of people diagnosed with type 2 diabetes mellitus after the age of 40 have positive islet cell cytoplasmic antibodies and GaD65 autoantibodies, which actually represent a subgroup of type 1 diabetes mellitus, also known as latent autoimmune diabetes (11). Although classically thought to primarily affect adults, type 2 diabetes mellitus also affects youths (14). In a recent analysis, prevalence was 15.9 per 1000 among 15- to 19-year-old Pima Indians, 4.5 per 1000 for all U.S. American Indians, and 2.3 per 1000 for Canadian Cree and Ojibway Indians in Manitoba (14). Thirty-three percent of all cases of diabetes mellitus among 10- to 19-year-old African Americans and Caucasians in Ohio were type 2 diabetes (14). These individuals tended to be obese, have a family history of type 2 diabetes, have acanthosis nigricans, belong to minority populations, and were more likely girls than boys (14). The Strong Heart Study looking at diabetes among American Indian tribes and communities showed age-adjusted diabetes rates to be 65 percent in men and 72 percent in women in tribes and communities in Arizona; 38 percent in men and 42 percent in women in Oklahoma; and 33 percent in men and 40 percent in women in South Dakota and North Dakota (15). Diabetes rates were positively associated with age, level of obesity, amount of Indian ancestry, and parental diabetes status

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(15). Rate of impaired glucose tolerance was 14 percent to 17 percent, which is similar to rates among the general U.S. population (15). Compared to their Caucasian counterparts, African American men are 20 percent to 50 percent more likely and African American women 100 percent more likely to have or develop diabetes (16). They are also at much higher risk for end-stage renal disease, lower-extremity amputation, and blindness (16). A cross-sectional study of three Mexican communities showed a higher prevalence in men compared to women (17). In younger adults, prevalence was 16.7 percent versus 9.5 percent in men compared to women; it was 30.8 percent versus 22.8 percent in older adults (17). Variables associated independently with diabetes in older people were gender (male sex: odds ratio [OR] = 2.1, p < 0.009); diminished carbohydrate intake (OR = 0.77, p < 0.03); central distribution of adiposity (OR = 1.9, p < 0.03); and functional disability (OR = 2.3, p < .01) (17). There seemed to be a higher prevalence of diabetes in urban versus rural populations (17). Approximately 52 percent of all persons aged ≥ 20 years with diabetes are women (18). A study looking at the socioeconomic status of women with diabetes suggests that women with diabetes were more likely to have a low socioeconomic status (18). Twenty-five percent of women with diabetes aged ≥ 25 years had lowlevel formal education, and 40 percent lived in low-income households (18). Women with diabetes (40.4 percent [95 percent confidence interval [CI] = 38.1 percent – 42.6 percent]) were twice as likely as women without diabetes (22 percent [95 percent CI = 21.5 percent – 22.5 percent]) to have an annual household income < $25,000 (18). Diabetes prevalence continues to increase quite rapidly. A 16 percent increase in prevalence was noted between 1980 and 1994, and a 33 percent increase between 1990 and 1998 (19, 20). The prevalence of diabetes seems highly correlated with the prevalence of obesity (21). On the basis of age, sex, and race, it is estimated that there will be a 225 percent projected increase in diabetes between 2000 and 2050, which means an increase from approximately 12 million to 39 million people diagnosed with diabetes in the U.S. (13). Other studies have estimated an increase ranging between 12 million to 29 million (19). Diagnosis of diabetes is expected to increase 460 percent in people 75 years of age or older, 241 percent among those 65 to 74 years old, 159 percent among those 45 to 64 years old, 125 percent among those 20 to 44 years old, and 97 percent among those 0 to 19 years old (13). Due to expected demographic changes, prevalence, and population growth, prevalence is expected to increase 149 percent among Hispanics, 118 percent among African Americans, and 104 percent among Caucasians (13).

III. DEFINING IMPAIRED GLUCOSE TOLERANCE, INSULIN RESISTANCE, AND DIABETES MELLITUS Impaired glucose tolerance (IGT), determined by the postload glucose value of the oral glucose tolerance test (OGTT), is found in individuals with moderately disturbed glucose metabolism (22). These individuals are generally hyperinsulinemic and have an increased risk of developing diabetes (22). The National Diabetes Data Group

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guidelines require at least one intermediate glucose level greater than 11.1 mmol/L for the diagnosis of IGT (22). According to current American Diabetes Association guidelines, a two-hour postload glucose ≥ 140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) is defined as impaired glucose tolerance (23). Insulin resistance, manifested by a diminished ability to keep glucose levels low with insulin levels in the normal range, precedes the onset of noninsulin-dependent diabetes mellitus. The glucose-clamp technique is the gold standard for the assessment of insulin resistance (22, 24). In individuals with insulin resistance, the glucose level is slightly raised, but remains below the diabetes range at the expense of raised insulin levels (22). Insulin resistance is thought to be a key factor in a cluster of cardiovascular risk factors (syndrome X or insulin resistance syndrome) (22). According to 1993 criteria, diabetes mellitus was diagnosed when plasma glucose exceeded 11.1 mmol/l (200 mg/dl) and classic symptoms of diabetes (polydipsia, polyuria, polyphagia, and weight loss) were present, or when the fasting plasma glucose exceeded 7.8 mmol/l (140 mg/dl) (22). If diabetes was not confirmed by these, but still suspected, an OGTT was performed (22). When a number of single glycemic measures are compared, the two-hour postload glucose level seems to be the best indicator of the presence of diabetes (22, 25, 26). The OGTT is a nonphysiologic procedure with high interperson variability (27). In a population of elderly people studied over a five-year period of time, the reliability coefficient of the diagnosis was 0.62 (27). Researchers have found that only 50 percent of OGTTs are reproducible (28). In patients that are diagnosed with impaired glucose tolerance on the first OGTT, only 40 percent to 60 percent are diagnosed with impaired glucose tolerance or diabetes on a second test (29–31). Therefore, epidemiologic studies based on a single OGTT may overestimate the prevalence of diabetes (22). More recent criteria regarding the diagnosis of diabetes include: classic symptoms of diabetes plus casual (casual defined as any time of day without regard to time since last meal) plasma glucose concentration ≥ 200 mg/dl; fasting (no caloric intake for at least eight hours) plasma glucose ≥ 126 mg/dl (7.0 mmol/l); and twohour plasma glucose ≥ 200 mg/dl during an OGTT using a glucose load containing the equivalent of 75 grams anhydrous glucose dissolved in water (23). There are two major types of diabetes: type 1 diabetes (5 percent to 10 percent of all diagnosed cases in the U.S.), which classically involves children and is primarily characterized by an absolute deficiency of insulin secretion; and type 2 diabetes (90 percent to 95 percent of all diagnosed cases), which is due to a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. There are several other, less common forms of diabetes (1 percent to 5 percent of all diagnosed cases), which result from genetic conditions, surgery, drugs, malnutrition, infections, and other illnesses (23, 32).

IV. DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS Prior to 1979, various criteria existed, and there was no consensus on how to diagnose diabetes (33). In 1979, the National Diabetes Data Group developed guidelines for diagnosing diabetes mellitus and impaired glucose tolerance, which were adopted

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by the American Diabetes Association in 1993 (33). According to these guidelines, diabetes was diagnosed when: 1) there was unequivocal elevation of plasma glucose (≥ 200 mg/dl [11.1 mmol/l]) and presence of classic symptoms of diabetes including polydipsia, polyuria, polyphagia, and weight loss; 2) fasting plasma glucose ≥ 140 mg/dl (7.8 mmol/l) on two occasions; 3) fasting plasma glucose less than 104 mg/dl and two OGTTs with the two-hour plasma glucose ≥ to 200 mg/dl and one intervening value ≥ 200 mg/dl after a 75-gram glucose load (33). Impaired glucose tolerance was defined by fasting plasma glucose less than 140 mg/dl and two-hour plasma ≥ 140 mg/dl, and less than 200 mg/dl with one intervening value ≥ 200 mg/dl after a 75-gram glucose load (33). The 1985 World Health Organization criteria use the fasting and two-hour values only, with fasting glucose ≥ to 140 mg/dl or two-hour glucose ≥ 200 mg/dl (33, 34). The 1997 American Diabetes Association criteria require fasting plasma glucose ≥ to 126 mg/dl (34). An International Expert Committee, established in May 1995, working under the auspices of the American Diabetes Association, published new recommendations in 2000 (23), as shown in Table 9.3. They stipulate that the diagnosis of diabetes mellitus should include one of these three criteria, namely classic symptoms of diabetes plus casual (casual defined as any time of day without regard to time since last meal) plasma glucose concentration ≥ 200 mg/dl; fasting (no caloric intake for at least eight hours) plasma glucose ≥ 126 mg/dl (7.0 mmol/l); or two-hour plasma glucose ≥ 200 mg/dl during an OGTT using a glucose load containing the equivalent of 75 grams anhydrous glucose dissolved in water (23). This expert committee defined: fasting plasma glucose < 110 mg/dl (6.1 mmol/l) as normal fasting glucose; fasting plasma glucose ≥ 110 mg/dl (6.1 mmol/l) and < 126 mg/dl (7.0 mmol/l) as impaired fasting glucose; and fasting plasma glucose > 126 mg/dl (7.0 mmol/l) as provisional diagnosis of diabetes (23). When OGTT is performed, a two-hour postload glucose < 140 mg/dl (7.8 mmol/l) is normal glucose

TABLE 9.3 American Diabetes Association 2000 Recommendations Regarding Diagnosis of Diabetes Mellitus

Diabetes Mellitus Normal fasting plasma glucose Impaired fasting plasma glucose Provisional diagnosis of diabetes mellitus

Classic Symptoms Plus Casual Plasma Glucose Concentrations ≥ 200 mg/dl (11.1 mmol/l) or Fasting Plasma Glucose ≥ 126 mg/dl (7.0 mmol/l) or 2-hour Plasma Glucose ≥ 200 mg/dl (11.1 mmol/l) during Oral Glucose Tolerance Test < 110 mg/dl (6.1 mmol/l) ≥ 110 mg/dl and < 126 mg/dl > 126 mg/dl (7.0 mmol/l)

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tolerance; a two-hour postload glucose ≥ 140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) is defined as impaired glucose tolerance; and a two-hour postload glucose ≥ 200 mg/dl (11.1 mmol/l) gives a provisional diagnosis of diabetes (23). There has been much debate regarding the impact of changes in methods of diagnosing diabetes on prevalence rates and on the number of nondiagnosed cases of diabetes. It is clear, however, that the current system of diagnosis is much more organized than it was prior to 1979.

V. RISK FACTORS A. GESTATIONAL DIABETES Gestational diabetes affects 0.6 percent to 15 percent of pregnant women (35). It implies an increased risk of development of impaired glucose tolerance and diabetes (35). Most develop type 2 diabetes, with an incidence of at least 13.8 percent. The incidence of type 1 diabetes is reported to be 0.7 percent to 6.6 percent over 2–11 years. In a study looking at gestational diabetes, the cumulative risk for diabetes and abnormal glucose tolerance was 13.8 percent and 42.4 percent after 11 years versus 0.0 and 2.8 percent in women without diabetes (35). Independent, predictive factors for diabetes were prior hyperglycemia; four abnormal glucose values on the diagnostic OGTT; overt diabetes during pregnancy; two-hour blood glucose ≥ 11.7 mmol/l on the diagnostic OGTT; gestational age at diagnosis < 24 weeks; and prepregnancy body-mass index (BMI) ≥ 26.4 kg/m2 (35). Race is thought to be a risk factor for gestational diabetes (36). Recurrence rates for gestational diabetes have been reported to range from 30 percent to 35 percent in studies looking at predominantly Caucasian populations, to ≥ 50 percent in nonwhite populations (36). Factors predictive of recurrent gestational diabetes include large infant birth weight, prepregnancy weight ≥ 190 pounds, and weight gain between pregnancies (36). The effect of additional pregnancies on the risk of future diabetes is controversial, with some studies suggesting an increased risk and others showing no increase (35). The range of relative risk (RR) for developing diabetes after gestational diabetes, in the literature, is 1.8 to 20.4 (37). In a carefully designed meta-analysis of controlled follow-up studies of women with gestational diabetes, the overall RR for developing diabetes after gestational diabetes was estimated to be 6.0 (95 percent, CI 4.1–8.8), with a population attributable risk of 0.10–0.31 (10 percent to 31 percent of cases of diabetes in parous women are associated with previous diabetes) (37).

B. POSTTRANSPLANTATION DIABETES Posttransplantation diabetes (PTDM) is, as the name implies, the development of diabetes after transplantation. Steroid diabetes was first reported in renal-transplant recipients (38). Its early frequency was 40 percent to 60 percent (38). The incidence ranges from 2 percent to 50 percent, with most cases being diagnosed within three months of transplantation (39, 40). Risk factors for posttransplant diabetes include age, non-Caucasian ethnicity (risk of posttransplantation diabetes is higher in African

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American recipients than Caucasian recipients), and immunosuppression (39). Transplant recipients with posttransplant diabetes tend to be 0 to 12 years older than those without (39). Non-Caucasian patients had a twofold increased risk of posttransplant diabetes (RR 3.3, 95 percent CI 1.7–7.0) (39). There is an increased incidence of posttransplant diabetes in patients treated with glucocorticoid therapy, cyclosporine, and those treated with high doses of tacrolimus (39, 41). The mean time from transplantation to development of PTDM is 1.2 years (range from one day to 6.2 years), with most cases occurring during the first three months after transplant or after treatment for rejection (41, 42). Significant risk-factor development of PTDM included: first-degree family history of type 2 diabetes mellitus, tacrolimus use, and hyperglycemia in the two weeks immediately after transplantation (42). Patients that developed persistent PTDM had later onset disease (mean 1.9 years) compared to those with transient PTDM (0.3 years) (42). Posttransplantation diabetes is associated with impaired long-term allograft survival and function. Reported six-year actuarial graft survival in one series was 67 percent in patients with PTDM versus 93 percent in control patients (38). Another series reported a 12-year graft survival of 48 percent for patients with PTDM versus 70 percent in control patients (38, 40). Cirrhosis is commonly associated with impaired glucose metabolism. Sixty to 80 percent of people with cirrhosis develop mild glucose intolerance associated with hyperinsulinism and increased insulin resistance (43). Diabetes mellitus develops in 10 percent to 30 percent of people with cirrhosis (43). Liver transplantation does not significantly modify pretransplant diabetes (43). Diabetes after liver transplant frequently develops de novo, is transient, and seems to be related primarily to immunosuppressive drug administration (43).

C. ASSOCIATION

OF

OBESITY

WITH

DIABETES

As extensively discussed in section I of this book, obesity and weight gain clearly seem to be associated with an increased risk of diabetes, although there are some studies that don’t show the association (44–46). Each year, 300,000 U.S. adults die of causes related to obesity (44). In 2000, the prevalence of obesity was 19.8 percent among U.S. adults (65.5 percent of men and 47.6 percent of women), which was a 61 percent increase from 1991 (44, 45). Weight gain, excess BMI, waist-hip ratio, and waist circumference are major risk factors for diabetes, with the waist circumference displaying the greatest relative risk (44, 47). In a national sample of adults, for every 1-kilogram increase in measured weight, the risk of diabetes increased by 4.5 percent (44). There seems to be an association between race and modification of diabetes risk by BMI, with African Americans having an increased risk at lower BMIs (i.e., adjusted RR for African Americans; for Caucasians, it was 2.83 for men and 3.13 for women at a BMI < 20 kg/m2) when compared to Caucasians, but an equivalent risk at high BMIs (at BMI ≥ 32 kg/m2, adjusted RR decreased to 1.14 for men and 1.09 for women) (48). The cause for this difference is not fully understood. One hypothesis is that the difference could be attributed to differences in fat distribution between African Americans and Caucasians (48).

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DIABETES

Studies examining effects of total fibers or types of fiber on self-reported incidence of diabetes have shown mixed results, with some showing no association and others showing inverse associations between diabetes risk and fiber intake (49). It has been well-established that carbohydrate intake can produce different glycemic responses, although there is some controversy surrounding the validity of the glycemic index and its use as a predictor of diabetes risk (49). Several studies have shown that fat intake is associated with impaired glucose metabolism (50), as reviewed in chapter 10 of this book. Glucose levels, insulin resistance, and hyperinsulinemia have been found to correlate with fat intake, particularly saturated fatty acids (50). Increased intake of vegetables and legumes is inversely associated with the development of impaired glucose tolerance or diabetes mellitus (50). The intake of vitamin C has been inversely associated with two-hour plasma glucose levels, although not completely understood (50).

E. DIABETES

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MICROALBUMINURIA

Microalbuminuria has been shown to be an important risk factor for cardiovascular disease and nephropathy in patients with type 2 diabetes (51). Meta-analysis has shown that the presence of microalbuminuria doubles the risk of cardiovascular morbidity or mortality and doubles the risk of total mortality (51). In patients with diabetes, the presence of microalbuminuria confers a tenfold higher risk of developing diabetic nephropathy annually, compared to patients without microalbuminuria (51). In a large cross-sectional analysis, when compared to patients with diabetes and normoalbuminuria, patients with diabetes and microalbuminuria had a longer duration of diabetes and higher waist-to-hip ratio, systolic and diastolic blood pressure, hemoglobin A1c (HbA1c), ankle-to-arm index, and serum creatinine (51). They were more likely to have a history of retinal laser therapy, hypertension, cerebrovascular disease, peripheral vascular disease, require insulin therapy, be smokers, and have electrocardiogram criteria for left-ventricular hypertrophy (51).

F. EFFECTS

OF

ALCOHOL

AND

CIGARETTES

Data from a prospective study of 87,938 subjects indicated that low to moderate consumption of alcohol is associated with decreased risk of coronary vascular disease in men with diabetes comparable to those without diabetes (52). There are several prospective cohort studies that suggest smoking is associated with the etiology of diabetes (53). In one study, the relative risk of type 2 diabetes in women smoking ≥ 25 cigarettes per year versus women who never smoked was 1.42 (95 percent CI, 1.18–1.72) (53). It was concluded that this suggested a moderate association between smoking and subsequent development of diabetes (53). In a similar study, the relative risk of type 2 diabetes in men smoking ≥ 25 cigarettes per year versus men who never smoked was 1.94 (95 percent CI, 1.25–3.03) (53). Furthermore, cigarette smoking has been associated with insulin resistance, larger

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upper-body fat distribution (a marker of insulin resistance), and raised plasmaglucose concentration (53). It has also been associated with blunting the rise of HbA1c (53). Cigarette smoking has been shown to be a significant risk factor for death by coronary artery disease in type 2 diabetes in several studies, including the Multiple Risk Factor Intervention Trial, The Finnish Prospective Study, and the Paris Prospective Study (53). Former smokers are 1.54 times (95 percent CI, 1.49–1.58) more likely to be diagnosed with coronary artery disease (53). Cigarette smoking has also been shown to be an independent predictor for stroke (53). It also appears to heighten the development of macrovascular and microvascular complications, including nephropathy and neuropathy (53). Its association with the development of retinopathy is not well-defined (53).

G. DIABETES

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PHYSICAL LIMITATIONS

People with diabetes have a higher prevalence of risk factors, such as obesity and sedentary behavior, and higher prevalence of health conditions, such as vision loss, depression, and cardiovascular disease, that are associated with physical limitations (54). In a nationwide, cross-sectional analysis, people with diabetes had a higher proportion of physical limitation than people without diabetes overall (66 percent versus 29 percent, p < 0.001), for men (59 percent versus 24 percent, p < 0.001), and women (72 percent versus 34 percent, p < 0.001) (54). The difference declined with increasing age: 18–44 years (46 percent versus 18 percent), 45–64 years (63 percent versus 35 percent), 65–74 years (74 percent versus 53 percent), and ≥ 75 years (85 versus 70 percent) (54). The OR for physical limitation among adults with diabetes versus adults without diabetes was 1.9 (95 percent CI, 1.8–2.1) (54). Although this association is not clearly defined, women seem to have a greater prevalence of physical limitations than men (54). In a national survey, 32 percent of women and 15 percent of men with diabetes versus 14 percent of women and 8 percent of men without diabetes reported inability to walk one-fourth of a mile, climb stairs, or do housework (55). There were two to three increased odds of not being able to do each task and up to 3.6-fold increased risk of not being able to do all three tasks associated with diabetes (55). Women with diabetes tend to have slower walking speed, inferior lower-extremity function, decreased balance, and increased risk of falling (55).

H. DIABETES

AND

MENTAL HEALTH

National surveys have reported that mentally ill people have worse health insurance and poorer access to care than people that are not mentally ill (56). A multicenter Veterans Administration hospital study, however, found little difference in the quality of diabetes care between those that were mentally ill and those that were not (56). This finding may be unique to that setting, owing to accessibility and monitoring of the level of care that occurs in that setting, and may not be reflective of national trends outside of the VA (56).

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VI. DIABETIC COMPLICATIONS A. CORONARY-VASCULAR DISEASE In 2000, 37.2 percent of people with diabetes age 35 years or older were diagnosed with cardiovascular disease (13). Prevalence of ischemic heart disease among people with diabetes was approximately 14 times that of those without diabetes in people 18 to 44 years of age (2.7 percent versus 0.2 percent), three times more in people 45 to 64 years of age (14.3 percent versus 4.7 percent), and approximately twice more in people 65 years of age or older (13). Classical risk factors for coronary artery disease include age, male gender, hypertension, and diabetes (57). The risk of clinical or isolated subclinical ischemic heart disease is more pronounced in women than men in older individuals, although there is a lower absolute prevalence, with an increased risk noted with the presence of diabetes (58, 59). Additional factors include diet and serum cholesterol, cigarette smoking, obesity, and sedentary lifestyle (57). The Framingham Study showed that smoking, hypertension, and elevated triglycerides were significant, independent predictors of coronary-vascular disease in patients with diabetes (60). A few studies have shown LDL cholesterol to be a significant, independent predictor of cardiovascular disease (60). Premature development and accelerated progression of macrovascular atherothrombotic disease is a major factor contributing to the high morbidity and mortality rates in diabetes (2). The relationship between hyperinsulinemia and the risk of cardiovascular disease is somewhat controversial, with articles both supporting and challenging this relationship (61–66). It still remains unclear whether the relationship is causal or whether the two diseases are causally unrelated, independent manifestations of an underlying disease state (2). Diabetes is well-established as an independent risk factor for the development of coronary-artery disease (2). Once a patient with diabetes develops clinical coronary-artery disease, cardiac complications occur with increased frequency, with diabetic patients with coronary-artery disease experiencing more morbidity and mortality than nondiabetic patients with coronary artery disease (67). Longitudinal studies looking at mortality from all causes, heart disease, and ischemic heart disease have shown that adults with diabetes experience less decline in their mortality rates than adults without diabetes (68). Diabetes has been shown to increase left ventricle wall thickness and mass (69). In the setting of ischemic heart disease, diabetes is associated with twice the incidence of acute coronary syndromes and a 1.5-fold to twofold increase in the incidence of death after myocardial infarction (2). Cardiovascular disease accounts for up to 80 percent of deaths in patients with diabetes, with approximately 75 percent of these deaths occurring as a result of ischemic heart disease (2). The most common cause of death is myocardial pump failure, and the second most common cause is myocardial reinfarction (70). The clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) study, which looked at the use of aspirin versus clopidogrel in patients with recent ischemic stroke, recent myocardial infarction (MI), or established peripheral vascular disease, showed an 8.7 percent relative risk reduction in vascular death, MI, or

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ischemic stroke with use of clopidogrel (54, 71). There was an additional 8.7 percent reduction noted in rehospitalization for ischemia or bleeding (54, 71). Postmenopausal women with diabetes have a twofold to fivefold increased risk of death from coronary-artery disease (72). Also, women who undergo simple hysterectomies and those who undergo bilateral oophorectomies have an increased risk of coronary-artery disease (72). In one study, women with diabetes who are prescribed hormonal-replacement therapy have been shown to be 40 percent less likely to suffer acute heart disease than women with diabetes who have never been prescribed hormonal-replacement therapy (72). Other studies, however, have shown no cardiovascular benefit from hormonal-replacement therapy (72). Women with insulin-treated diabetes were found to be more likely to develop coronary-artery disease than women treated with oral hypoglycemic medication or diet alone (72).

B. PERIPHERAL NEUROPATHY

AND

PERIPHERAL VASCULAR DISEASE

The health-care cost of problems related to the diabetic foot, the most common cause of hospitalization in patients with diabetes, is estimated to be more than $1 billion annually (73). In 2003, the total annual cost of diabetic peripheral neuropathy and its complications were estimated to be between $4.6 and $13.7 billion (74). In large cohort studies, prevalence rates for neuropathy have ranged from 7.5 percent at time of diagnosis of diabetes, to 50 percent 25 years after initial diagnosis (75). It is present in more than 80 percent of diabetic patients with foot lesions (73). Poor glycemic control is associated with an increased risk for neuropathy and amputation (76). In one study, a HbA1c > 13.4 was associated with 2.2 relative risk of amputation (76). In another study, a 50 mg/dl increase in the mean random glucose was associated with a 1.6 OR for amputation (76). Diabetic peripheral neuropathy predisposes to foot ulceration and lower-extremity amputation (74). The presence of peripheral neuropathy is associated with eightfold to eighteenfold higher risk of ulceration and twofold to fifteenfold higher risk of amputation (76). The incidence of self-reported foot ulcers in people with diabetes is 2.4 percent to 2.6 percent per year (76). The prevalence of foot ulcers ranges from 4 percent to 10 percent, and it is estimated in the U.S. that 15 percent of patients with diabetes will develop foot ulceration at least once during their lifetime (74, 76, 77). While vascular disease does play a role, 60 percent to 70 percent of diabetic foot ulcers are neuropathic in origin (74). It is also estimated that approximately 85 percent of all diabetic lower-extremity amputations are preceded by a nonhealing foot ulcer (76). It is estimated that 45 percent of lower-limb amputations are done on people with diabetes, with the relative probability of lower-extremity amputation reported to be as high as 27 times more likely among patients with diabetes (78, 79). The risk of diabetic ulcers and lower-extremity amputation increases twofold to fourfold with age and duration of diabetes (76). Most studies of people with type 2 diabetes have shown a 1.6 increased risk of lower-extremity ulcers and a 2.8-fold to 6.5-fold higher risk of amputation associated with male sex (76). Lack of patient education on foot care is associated with a 3.2 increased risk of amputation (76). A comprehensive review showed that in the U.S. between 1989 and 1993, the

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prevalence of amputations was 1.6 percent for people age 18–44 years, 2.4 percent for people age 45–64 years, and 3.6 percent for people ≥ 65 years old (76). A statewide analysis performed in California showed Hispanics to have proportionally more amputations associated with diabetes than African Americans or nonHispanic whites (82.7 percent versus 61.6 percent versus 56.8 percent) (80). Overall, however, the incidence of diabetes-related, lower-extremity amputations was higher in African Americans at every level of amputation (80). The level of amputation was: toe (19.9–41.02 percent); foot (3.58–12.91 percent); leg (12.25–37.07 percent); and thigh (4.29–18.73 percent) (80). A retrospective review of patients admitted to a university hospital showed that patients admitted with diabetic foot ulceration underwent less-than-adequate foot examinations, with 31.4 percent not having documentation of pedal pulses, 59.7 percent not being evaluated for presence of protective sensation, 90 percent of wounds not evaluated for involvement of underlying structures, and 32.9 percent not having foot radiographs (81). This study highlighted the need for a systematic, detailed lower-extremity examination for every patient with diabetes admitted to a hospital (81). Patients with extremity infections should also be carefully evaluated for the presence of undiagnosed diabetes mellitus (82). In a large retrospective study, 17.2 percent of all patients seen with extremity infections had previously undiagnosed diabetes mellitus, with 12.1 percent having lower-extremity infections (82). Other studies have reported a 3 percent to 7 percent incidence of newly diagnosed diabetes in people presenting with extremity infections (82).

C. CEREBROVASCULAR DISEASE People with diabetes are at increased risk for cerebrovascular events (83). The estimated relative risk for patients with diabetes was initially reported to be 2.5-fold to 3.5-fold greater in diabetic patients that were aged 45 to 74 in the Framingham study (83). It was later modified to 1.4 for diabetic men and 1.72 for diabetic women after adjusting for other known risk factors (84). Diabetes was found to be responsible for 16 percent of stroke deaths in men and 33 percent in women, in a study reviewing stroke mortality (85). In a stroke-survival study, the 30-day survival rate was 89 percent in men and 79 percent in women; one-year survival was 79 percent for men and 64 percent for women (86). There may be specific patterns of stroke associated with diabetic patients. Review of a prospective, community-based registry showed that diabetes mellitus was associated with a lower relative prevalence of intracerebral hemorrhage (OR [95 percent CI]:0.63 (0.45 to 09.9); p = 0.022), higher relative prevalence of subcortical infarction (1.34 [1.11 to 1.62]; p = 0.009), and higher relative frequency of small-vessel disease (1.78 [1.31 to 3.82]; p = 0.012) and large-artery disease (2.02 [1.31 to 2.02] p = 0.002) (87). There was, however, no significant difference in the level of moderate to severe deficit on admission (31.1 percent versus 31.6 percent; p = 0.4) and poor functional outcome at one month (14.1 percent versus 15.3 percent; p = 0.24) when comparing patients with diabetes mellitus to patients who do not have the disease (87). A European study evaluating diabetes in 937 patients revealed that patients

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with diabetes were more likely to have limb weakness (p < 0.02), dysarthria (p < 0.001), ischemic stroke (p << 0.001), and lacunar cerebral infarction (p = 0.03) (88). Handicap (Rankin scale) disability (Barthel Index) was significantly higher in patients with diabetes (p = 0.005 and p = 0.016) (88).

D. ERECTILE DYSFUNCTION Diabetes has been associated with the development of erectile dysfunction since 1798 (89). The OR of having erectile dysfunction if a man is diabetic is 1.9 to 4 times greater than in men without diabetes, and it is estimated that 25 percent to 75 percent of men with type 1 diabetes will complain of erectile dysfunction (89). There is an age association with the development of erectile dysfunction, with 15 percent of diabetic men having erectile dysfunction by age 30 and 55 percent by age 60 (89). The mechanism of diabetes-induced erectile dysfunction is multifactorial (89). Related causes include smooth-muscle dysfunction, endothelial dysfunction, and neuropathic damage (89).

E. DIABETIC NEPHROPATHY The National Health and Nutrition Examination Survey found an incidence of endstage renal disease of 0.23/100 person years, with rates of 0.29 for patients with type 1 diabetes and 0.27 for patients with type 2 diabetes (90). Factors such as African American race, gout, and hypertension more than doubled the risk of endstage renal disease (90). In a study by Klein et al., analyzing 891 patients with type 1 diabetes, the 10-year cumulative incidence of renal failure or serum creatinine > 2.0 mg/dl was 14.9 percent (90). The risk of renal failure almost doubled for every 1 percent increase in HbA1c (36). Hypertension almost tripled the risk (90).

F. RETINOPATHY Diabetes can lead to multiple eye pathologies, including retinopathy, certain lens opacities, increased intraocular pressure, rubeosis iridis, and possibly open-angle glaucoma (91). The association between diabetes and open-angle glaucoma is controversial, with several studies demonstrating an association but several other large studies failing to demonstrate any association (92). Retinopathy affects more than 300,000 people in the U.S. (90). It is the leading cause of blindness in people age 20 to 64 years old (13). It accounts for 12 percent of all new cases of blindness, with 12,000 to 24,000 new cases each year in the U.S. (13). The prevalence of diabetic retinopathy is 46 percent higher in non-Hispanic blacks and 84 percent higher in Mexican Americans compared to non-Hispanic Caucasians (93). There is evidence to suggest that retinopathy begins to develop at least seven years before type 2 diabetes is clinically diagnosed (94, 95). The Wisconsin Epidemiologic Study of Diabetic Retinopathy examined the prevalence and incidence of diabetic retinopathy (91). The pathogenesis of retinopathy is thought to begin with hyperglycemia, which leads to increased levels of protein kinase C and aldose reductase activities, nonenzymatic glycosylation, vasoactive substances, growth factors, and free radicals (90, 96). These changes cause functional changes,

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such as increased vitreous fluorometry and abnormal electrical conductance (90). They also cause anatomic changes (90). Glycemic control, as measured by glycosylated hemoglobin, and not C-peptide secretion or the type of diabetes, seems to be the most important predictor of diabetic complications, such as retinopathy (8, 96–98). Retinopathy incidence increases above a fasting plasma glucose of ≥ 126 mg/dl (96, 99). The Wisconsin Epidemiologic Study of Diabetic Retinopathy, which studied > 900 patients aged < 30 at onset of diabetes, showed 20 percent of patients at age 15 were affected by retinopathy, 60 percent at age 20, and 80 percent at age 30 (90). The risk of retinopathy increased 50 percent for every 1 percent increase in HbA1c, for every 10-mm Hg increase in systolic blood pressure, and for every three years’ diabetes duration (90). The findings in the Wisconsin Epidemiologic Study of Diabetic Retinopathy were similiar to those found in the concurrently run Diabetes Control and Complications Trial (98). A population-based cohort study showed a modest increased risk of incidence of diabetic retinopathy in patients with younger-onset diabetes and hypertension (10 years after the baseline examination) [OR, 1.27; 95 percent CI, 1.03–1.57] (100). There was no consistent association of blood pressure and retinopathy in subjects with older-onset diabetes (100).

G. DENTAL DISEASE Dental complications of diabetes mellitus include severe periodontitis and subsequent tooth loss, gingivitis, dental abscesses, xerostomia, and soft-tissue lesions of the tongue and oral mucosa, such as candidiasis (101). Routine, preventive dental care may be important in preventing and treating these complications. A large crosssectional study, however, showed that dentate adults with diabetes were less likely to see a dentist than those without diabetes (65.8 percent versus 73.1 percent, p = 0.0000) (101).

VII. MORTALITY The development of diabetes seems to predict premature mortality (102). In 2000, diabetes was listed as the sixth leading cause of death in the U.S. (13). It is estimated that approximately 17 percent of Americans age 25 years and older who die have diabetes (13). A cross-sectional study revealed mortality rates of 41.8 per 1000 for the diabetic population in comparison to 10.1 per 1000 for the nondiabetic population (102). The risk of mortality relative to the nondiabetic population decreased with age (102). The increased risk for death associated with diabetes is 3.6:1 for people age 25 to 44 years and 1.5:1 for people age 65 to 74 years (13). Males with diabetes lost an average of 7.0 years from the year of diagnosis, and females with diabetes lost an average of 7.5 years (102). Sixty-five percent of all deaths in people with diabetes in the U.S. are reported to be due to cardiovascular disease (13).

VIII. LEVEL OF HEALTH CARE In a study looking at African Americans, Hispanics, and non-Hispanic Whites, they were found to be equally likely to receive treatment for diabetes (103). However,

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African Americans were more likely to have poorly controlled diabetes (HbA1c > 8.0 percent, OR 2.23, 95 percent CI 1.26–3.94) (103). A cross-sectional study suggests that underuse of recommended preventive-care practices is common among people with diabetes (48). Among this population, 78 percent practiced self-monitoring of blood glucose, 72 percent visited a health-care provider at least once in a 12-month period, 61 percent had their blood glucose examined at least once per year, and 61 percent received a dilated eye examination (48).

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