Insulin Resistance Syndrome and Neuropsychiatric Disease (Medical Psychiatry)

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Psychiatry

The first book of its kind to tie the metabolic syndrome with psychiatric disorders, and the possibility that common antipsychotic treatments may be having an adverse effect on patients. Insulin Resistance Syndrome and Neuropsychiatric Disease describes: • insulin resistance syndrome • psychiatric and cognitive disorders • impact of treatment of psychiatric disorders on metabolic function • insulin resistance as a link between affective disorders and Alzheimer’s disease And also examines: • the metabolic syndrome, including its relationships with diseases of the central nervous system, as well as new treatments to help prevent metabolic complications among patients with neuropsychiatric illnesses Presenting a complete overview and the relationship between insulin resistance syndrome, and psychiatric and cognitive disorders, Insulin Resistance Syndrome and Neuropsychiatric Disease will be a welcome update to any psychiatrist’s, neurologist’s, endocrinologist’s, and research scientist’s library. about the editor... NATALIE L. RASGON is Professor, Departments of Psychiatry and Behavioral Sciences, Obstetrics and Gynecology, Stanford University, California, and she is Director of the Center for Neuroscience in Women’s Health at the Stanford School of Medicine and Stanford Neuroscience Institute. Dr. Rasgon received her M.D. and Ph.D. in Obstetrics and Gynecology and Pathological Physiology from the Central Institute of Postgraduate Medical Education, Central Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences, Moscow, Russia. Dr. Rasgon is the author of over 124 peer-reviewed articles, more than 25 book chapters, and is a reviewer for more than 25 medical journals specific to psychiatry, neuropharmacology, and obstetrics and gynecology. Printed in the United States of America

InsulIn ResIstance syndRome and neuRopsychIatRIc dIsease

about the book…

InsulIn ResIstance syndRome and neuRopsychIatRIc dIsease Medical Psychiatry Series / 38

Edited by

Natalie L. Rasgon, M.D., Ph.D. Rasgon

$+

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Insulin Resistance Syndrome and Neuropsychiatric Disease

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Medical Psychiatry Series Editor Emeritus

William A. Frosch, M.D. Weill Medical College of Cornell University New York, New York, U.S.A. Advisory Board Jonathan E. Alpert, M.D., Ph.D.

Siegfried Kasper, M.D.

Massachusetts General Hospital and Harvard University School of Medicine Boston, Massachusetts, U.S.A.

Medical University of Vienna Vienna, Austria

Mark H. Rapaport, M.D. Bennett Leventhal, M.D. University of Chicago School of Medicine Chicago, Illinois, U.S.A.

Cedars-Sinai Medical Center Los Angeles, California, U.S.A.

1. Handbook of Depression and Anxiety: A Biological Approach, edited by Johan A. den Boer and J. M. Ad Sitsen 2. Anticonvulsants in Mood Disorders, edited by Russell T. Joffe and Joseph R. Calabrese 3. Serotonin in Antipsychotic Treatment: Mechanisms and Clinical Practice, edited by John M. Kane, H.-J. Mo¨ller, and Frans Awouters 4. Handbook of Functional Gastrointestinal Disorders, edited by Kevin W. Olden 5. Clinical Management of Anxiety, edited by Johan A. den Boer 6. Obsessive-Compulsive Disorders: Diagnosis . Etiology . Treatment, edited by Eric Hollander and Dan J. Stein 7. Bipolar Disorder: Biological Models and Their Clinical Application, edited by L. Trevor Young and Russell T. Joffe 8. Dual Diagnosis and Treatment: Substance Abuse and Comorbid Medical and Psychiatric Disorders, edited by Henry R. Kranzler and Bruce J. Rounsaville 9. Geriatric Psychopharmacology, edited by J. Craig Nelson 10. Panic Disorder and Its Treatment, edited by Jerrold F. Rosenbaum and Mark H. Pollack 11. Comorbidity in Affective Disorders, edited by Mauricio Tohen 12. Practical Management of the Side Effects of Psychotropic Drugs, edited by Richard Balon 13. Psychiatric Treatment of the Medically III, edited by Robert G. Robinson and William R. Yates

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14. Medical Management of the Violent Patient: Clinical Assessment and Therapy, edited by Kenneth Tardiff 15. Bipolar Disorders: Basic Mechanisms and Therapeutic Implications, edited by Jair C. Soares and Samuel Gershon 16. Schizophrenia: A New Guide for Clinicians, edited by John G. Csernansky 17. Polypharmacy in Psychiatry, edited by S. Nassir Ghaemi 18. Pharmacotherapy for Child and Adolescent Psychiatric Disorders: Second Edition, Revised and Expanded, David R. Rosenberg, Pablo A. Davanzo, and Samuel Gershon 19. Brain Imaging In Affective Disorders, edited by Jair C. Soares 20. Handbook of Medical Psychiatry, edited by Jair C. Soares and Samuel Gershon 21. Handbook of Depression and Anxiety: A Biological Approach, Second Edition, edited by Siegfried Kasper, Johan A. den Boer, and J. M. Ad Sitsen 22. Aggression: Psychiatric Assessment and Treatment, edited by Emil Coccaro 23. Depression in Later Life: A Multidisciplinary Psychiatric Approach, edited by James Ellison and Sumer Verma 24. Autism Spectrum Disorders, edited by Eric Hollander 25. Handbook of Chronic Depression: Diagnosis and Therapeutic Management, edited by Jonathan E. Alpert and Maurizio Fava 26. Clinical Handbook of Eating Disorders: An Integrated Approach, edited by Timothy D. Brewerton 27. Dual Diagnosis and Psychiatric Treatment: Substance Abuse and Comorbid Disorders: Second Edition, edited by Henry R. Kranzler and Joyce A. Tinsley 28. Atypical Antipsychotics: From Bench to Bedside, edited by John G. Csernansky and John Lauriello 29. Social Anxiety Disorder, edited by Borwin Bandelow and Dan J. Stein 30. Handbook of Sexual Dysfunction, edited by Richard Balon and R. Taylor Segraves 31. Borderline Personality Disorder, edited by Mary C. Zanarini 32. Handbook of Bipolar Disorder: Diagnosis and Therapeutic Approaches, edited by Siegfried Kasper and Robert M. A. Hirschfeld 33. Obesity and Mental Disorders, edited by Susan L. McElroy, David B. Allison, and George A. Bray 34. Depression: Treatment Strategies and Management, edited by Thomas L. Schwartz and Timothy J. Petersen 35. Bipolar Disorders: Basic Mechanisms and Therapeutic Implications, Second Edition, edited by Jair C. Soares and Allan H. Young 36. Neurogenetics of Psychiatric Disorders, edited by Akira Sawa and Melvin G. Mclnnis 37. Attention Deficit Hyperactivity Disorder: Concepts, Controversies, New Directions, edited by Keith McBurnett, Linda Pfiffner, Russell Schachar, Glen Raymond Elliot, and Joel Nigg 38. Insulin Resistance Syndrome and Neuropsychiatric Disease, edited by Natalie L. Rasgon

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Insulin Resistance Syndrome and Neuropsychiatric Disease

Edited by

Natalie L. Rasgon, M.D., Ph.D. Stanford University Stanford, California, USA

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Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 # 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-8208-4 (Hardcover) International Standard Book Number-13: 978-0-8493-8208-6 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Insulin resistance syndrome and neuropsychiatric disease / edited by Natalie L. Rasgon. p. ; cm. — (Medical psychiatry; 38) Includes bibliographical references and index. ISBN-13: 978-0-8493-8208-6 (hb : alk. paper) ISBN-10: 0-8493-8208-4 (hb : alk. paper) 1. Metabolic syndrome— Complications. 2. Mental illness—Complications. 3. Alzheimer’s disease— Complications. I. Rasgon, Natalie L. II. Series. [DNLM: 1. Metabolic Syndrome X—complications. 2. Alzheimer Disease— complications. 3. Mental Disorders—complications. W1 ME421SM v.38 2008/ WK 820 M5868 2008] RC662.4.M52 2008 616.30 99—dc22 2007045871 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Preface

A great deal has been written about current medical foes in our society. Obesity, diabetes, depression, and dementia are all critical health issues with ramifications beyond the physical health of our nation. In the United States, obesity and diabetes have reached epidemic levels, not only among adults, but also among children and adolescents. In 1990, the rate of depression was estimated at 11 million people, and the estimate of the annual cost of depression was $44 billion (1). The rate of depression in any given year is estimated to be 9.5% (2), and with an estimated population of 301,139,947 million, this estimate has enormous implications for the economy and the mental and physical health of our nation. The growing rates of depression in the United States are already reflected in the use of psychotropic medications, as antidepressants are the most often prescribed medications in the United States. Finally, as the population in the United States and the western world ages, the rate of dementia grows precipitously, doubling after age 85. These statistics only highlight the growing concern of the effects of physical and psychological illness and the critical need for new research and funding on the proper diagnosis and treatment of illnesses. It is estimated that approximately 50% of the population aged 50 years and older have a diagnosis of major depression. Four million adults in the United States alone carry a diagnosis of dementia and 16 million have diabetes. It is not a coincidence then that these three Ds (diabetes, depression, and dementia) are iii

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so prevalent in our society. There are numerous biological and psychosocial explanations to them, and this book is focused on the biological concepts of these diseases. The aim is to educate clinicians of all specialties on pathophysiology and interrelationship among the three Ds, in order to formulate optimal approaches to their diagnosis and treatments. As will be described in this book, bidirectional relationships exist between diabetes and depression and depression and dementia. There is also a notion of Alzheimer’s disease being a form of diabetes of the brain. Because of this degree of reciprocity between the brain and the body (soma), it is plausible to postulate that depressive illness is not just a psychiatric disease—as diabetes is not just an endocrine disorder, nor that dementia is just a neurodegenerative disease per se—but that all of these diseases represent complex psychoneuroendocrine conditions requiring a complex multisystem approach to their prevention and treatment. Though this concept may seem obvious, is not firmly established as a thinking paradigm in the clinical community. This book will thus serve as a resource and a guide to development of early diagnoses and interventions among afflicted individuals with one or more of these three Ds to protect them from damage and irreversible changes. Metabolic syndrome refers to a cluster of symptoms that increase the risk of morbidity and mortality from cardiovascular disease and diabetes (3). As such, this nosology has been a subject of intense debate with regard to its definitions causality or utility in clinical psychiatry. Part of the complexity regarding metabolic syndrome is the fact that there is not a single internationally agreed-upon definition. As such, we have included a chapter by Gerald Reaven, the father of Syndrome X, which provides an elegant overview of insulin resistance syndrome and an argument for its superior clinical relevance in lieu of metabolic syndrome. As mentioned above, the findings from several areas of research suggest that there is a link between depression and the risk of dementia. In retrospective studies of patients with Alzheimer’s disease, a history of depression has been found to be associated with late-onset Alzheimer’s disease (4–6). In prospective community sample studies, depressive symptoms at the baseline evaluation were associated with an increased risk of

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incident dementia (7,8). Likewise, a fair number of patients with depression have been found to develop dementia (9–12). Long-standing—especially, poorly controlled—diabetes has been shown to cause both diffuse and focal changes in the brain, which are manifested as cognitive decline. These effects are mediated by metabolic disturbances on neurons as well vascular disease and hypertension. In turn, diabetes is closely associated with depressive symptoms and depressive disorders, with comorbidity ranging between 40% and 70% (13). Cognitive declines are also commonly present among patients with primary affective disorders and are unrelated to psychosocial consequences of living with a chronic disease. The reciprocal links between the nervous system and endocrine systems underlie changes in the brain and body in both depressive illness and diabetes. Depressive disorder is associated with blunted central serotonin release (13), which, in turn, has been associated with metabolic dysfunction (14). If the metabolic dysfunction is associated with increased risk of developing cognitive impairment and, ultimately, dementia, then early identification and treatment of these conditions may offer avenues for primary prevention of neurodegenerative illness. Another possible mechanism for adverse consequence of insulin resistance in the central nervous system is a high level of inflammation. Specifically, inflammatory processes are widely implicated in the pathophysiology of diabetes and cardiovascular disease, as well as in cognitive impairment. Among the suggested explanations are the independent effects of atherosclerosis and associated inflammation on cognitive decline (15), although metabolic dysfunction and inflammation may have cumulative effect on vasculature, manifested by changes in periphery (cardiovascular disease) and central nervous system (cognitive decline). Our last chapter provides an overview and synthesis of the major connecting links between insulin resistance and other aspects of brain function. Several other mediators of the reciprocal interaction between the CNS and insulin resistance include glucocorticoids (cortisol), insulin, serotonin, and glutamate among others. The concept of a final common pathway can be applied to these interactions, as the most likely place of convergence in action of

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these biomarkers is the hippocampus. Specifically, the hippocampus is a central brain structure involved in regulation of mood and cognition and is specifically sensitive to cortisol, insulin, serotonin, and other neuromediators. A number of chapters in this monograph will address the anatomy and physiology of hippocampus with an emphasis on the integration of various influences in the three Ds. While insulin affects hippocampal structures involved in body weight regulation (16), it also it influences memory processing (17–25). There are central insulin receptors predominantly located in the hippocampus and adjacent limbic structures (26,27). Currently, the investigation of intranasal administration of insulin is promising, as it specifically targets hippocampal function. In fact, studies have suggested improvement in hippocampal–specific declarative memory upon intranasal administration of insulin. Though, it should be noted that such improvements may be the result of the effects of insulin on cortisol concentrations. In addition, cortisol is a well-known endotoxin with regard to hippocampal neurons, by binding to hippocampal glucocorticoid receptors, inhibiting synaptic longterm potentiation and decreasing hippocampal glutamate turn over (28). Therefore, a decrease in cortisol may be behind improving effects of insulin on hippocampal functioning (29). Finally, even as the neurodegeneration ensues, the impaired metabolic processes may be modulated to affect the disease course. In the chapter by Craft and colleagues, their current findings on the role of insulin resistance in patients with Alzheimer’s disease offer potential ways to modify this dysfunction. Certainly, lifestyle and other modifiable risk factors are attractive methods for disease prevention and overall wellness. Nevertheless, it is as important to be knowledgeable about the intricate links behind the disease formation, as it is to offer patients nonpharmacological interventions at an earlier stage when the impact is not as pronounced. With that, I highly recommend this volume and hope that the reader will find it not only informative, but provocative of new research directions in solving a fascinating puzzle of the three Ds. Natalie L. Rasgon

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References 1. Greenberg PE, Stiglin LE, Finkelstein SN, et al. The economic burden of depression in 1990. J Clin Psychiatry 1993; 54(11): 405–418. 2. Robins LN, Regier DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York: The Free Press, 1990. 3. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middleaged men. JAMA 2002; 288(21):2709–2716. 4. Jorm AF, van Duijn CM, Chandra V, et al. Psychiatric history and related exposures as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 1991; 20(suppl 2):S43—S47. 5. Speck CE, Kukull WA, Brenner DE, et al. History of depression as a risk factor for Alzheimer’s disease. Epidemiology 1995; 6(4): 366–369. 6. Steffens DC, Plassman BL, Helms MJ, et al. A twin study of lateonset depression and apolipoprotein E epsilon 4 as risk factors for Alzheimer’s disease. Biol Psychiatry 1997; 41(8):851–856. 7. Devanand DP, Sano M, Tang MX, et al. Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry 1996; 53(2):175–182. 8. Schmand B, Jonker C, Geerlings MI, et al. Subjective memory complaints in the elderly: depressive symptoms and future dementia. Br J Psychiatry 1997; 171:373–376. 9. Rabins PV, Merchant A, Nestadt G. Criteria for diagnosing reversible dementia caused by depression: validation by 2-year follow-up. Br J Psychiatry 1984; 144:488–492. 10. Alexopoulos GS, Meyers BS, Young RC, et al. The course of geriatric depression with ‘‘reversible dementia’’: a controlled study. Am J Psychiatry 1993; 150(11):1693–1699. 11. Stoudemire A, Hill CD, Morris R, et al. Long-term affective and cognitive outcome in depressed older adults. Am J Psychiatry 1993; 150(6):896–900.

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12. Stoudemire, Stoudemire A, Hill CD, et al. Improvement in depression-related cognitive dysfunction following ECT. J Neuropsychiatry Clin Neurosci 1995; 7(1):31–34. 13. Zhao W, Chen Y, Lin M, et al. Association between diabetes and depression: sex and age differences. Public Health 2006; 120(8): 696–704. 14. Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet 2006; 367(9505): 153–167. (Review). 15. Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292(18): 2237–2242. 16. Porte D Jr., Woods SC. Regulation of food intake and body weight in insulin. Diabetologia 1981; 20(suppl):274–280. 17. Marfaing P, Penicaud L, Broer Y, et al. Effects of hyperinsulinemia on local cerebral insulin binding and glucose utilization in normoglycemic awake rats. Neurosci Lett 1990; 115(2–3):279–285. 18. Craft S. Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 2007; 4(2):147–152. 19. Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord 2006; 20(4):298–301. 20. Craft S. Insulin resistance syndrome and Alzheimer’s disease: ageand obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 2005; 26(suppl 1):65–69. (Epub 2005 Nov 2). 21. Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003; 28(6):809–822. 22. Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci 2000; 903:222–228.

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23. Craft S, Asthana S, Newcomer JW, et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 1999; 56(12):1135–1140. 24. Craft S, Asthana S, Schellenberg G, et al. Insulin metabolism in Alzheimer’s disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology 1999; 70(2):146–152. 25. Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 1991; 36(5):343–362. 26. Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998; 112(5):1199–1208. 27. Sapolsky RM. Potential behavioral modification of glucocorticoid damage to the hippocampus. Behav Brain Res 1993; 57(2):175–182. (Review). 28. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004; 29(10):1326–1334.

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Contents

Preface . . . . . . . . . . . . . . . . iii Contributors . . . . . . . . . . . . xiii 1.

2.

3.

4.

The Metabolic Syndrome: Much Ado About (Almost) Nothing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerald Reaven Insulin Resistance in Schizophrenia, Major Depression, and Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . Steven E. Lindley, Carmen M. Schro¨ der, Ruth O’Hara, and Sergio Fazio Insulin Resistance Syndrome and Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . Kristoffer Rhoads and Suzanne Craft

1

49

87

Insulin Resistance Link Between Depressive Disorders and Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . 103 Heather A. Kenna, Margaret F. Reynolds, Bowen Jiang, and Natalie L. Rasgon

Index . . . . 139

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Contributors

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, U.S.A. Suzanne Craft

Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. Sergio Fazio

Bowen Jiang Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A. Heather A. Kenna Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Steven E. Lindley

Ruth O’Hara Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Natalie L. Rasgon

Gerald Reaven Department of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, U.S.A. xiii

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Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Margaret F. Reynolds

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, U.S.A.

Kristoffer Rhoads

Carmen M. Schro¨der Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

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1 The Metabolic Syndrome: Much Ado About (Almost) Nothing GERALD REAVEN Department of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, U.S.A.

1

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The Metabolic Syndrome: Much Ado About (Almost) Nothing

3

INTRODUCTION The past several years have witnessed a veritable frenzy of activity focused on a diagnostic category designated as the metabolic syndrome (MetS). At least three different sets of criteria have been published with which to make this diagnosis (1–3), and literally hundreds of papers have been published in the past few years using these definitions to describe the prevalence of the MetS in an almost infinite number of different populations and/or their relative ability to identify person at risk to develop cardiovascular disease (CVD) or type 2 diabetes mellitus (2DM) (4). Despite this publication onslaught, questions have been raised as to both the pedagogical utility of the various definitions, as well as the clinical relevance of deciding whether or not an individual meets the diagnostic criteria for the MetS (4–7). The goal of this presentation will be to address both of these issues.

THE METS AS A PATHOPHYSIOLOGICAL CONSTRUCT The three definitions of the MetS share many common attributes. Perhaps the most important one is that they are all the products of consensus conferences, in which a number of ‘‘thought leaders’’ have met, interacted, and produced definitions of a new diagnostic category. Thus, neither the criteria selected to serve as the basis of diagnosing the MetS nor the values of the cut points that constitute an abnormality are evidence based. The specific components that have been selected to serve as diagnostic criteria by the three versions of the MetS are also similar, but the manner in which they are used is quite different. For example, is there a biological connection that links the individual diagnostic criteria of the MetS to each other, and, if so, is the relationship hierarchical in nature? Conversely, are the individual components simply CVD risk factors that have no physiological relationship with each other, i.e., they cluster together for no discernible reason? A discussion of these issues will be the focus in this section.

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4

Reaven

World Health Organization The World Health Organization (WHO) was the first major organization to propose a set of clinical criteria for the MetS, formalized and published (1) in a document titled ‘‘Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications.’’ The primary purpose of this report was to update the classification and diagnostic criteria of diabetes mellitus. In this context, the WHO Consultation Group designated the MetS as a special classification for individuals with 2DM or with the potential for developing 2DM: manifested by having impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or insulin resistance by hyperinsulinemic, euglycemic clamp. The WHO Consultation Group felt that once these individuals developed certain ‘‘CVD risk components,’’ they became a unique entity and qualified as having the MetS. Aside from glucose tolerance status and/or insulin resistance, risk components deemed useful to identify individuals with the MetS included obesity, dyslipidemia, hypertension, and microalbuminuria. It was the view of the WHO Consultation Group that each component conveyed increased CVD risk but as a combination became more ‘‘powerful.’’ Therefore, the primary goal of recognizing an individual as having the MetS was to identify persons at undue risk for CVD. Secondarily, by design, the diagnosis also helped identify individuals with high risk for diabetes if they did not already have it. Table 1 displays the criteria proposed by the WHO to make a diagnosis of the MetS. The components that make up the WHO definition of the MetS are hierarchical in that one component, insulin resistance, must be present to make this diagnosis. However, there are four ways in which this essential criterion can be satisfied. The most direct path to identify insulin resistance is to perform a hyperinsulinemic, euglycemic clamp study, an approach that has no clinical utility. Consequently, some form of glucose intolerance must be present to document insulin resistance: 2DM, IGT, or IFG. There is no doubt that the prevalence of insulin resistance is greatly increased in subjects with 2DM or IGT (8–14), but the need to measure plasma glucose concentration 120 minutes after an oral glucose load decreases the clinical utility of IGT to satisfy the essential WHO criterion for insulin resistance. Although the

Abbreviation: HDL-C, high-density lipoprotein–cholesterol.

Plus any two of following: l Waist/hip ratio > 0.9 in men, > 0.85 in women, and/or BMI > 30 kg/m2 l Triglycerides
1.7 mmol/L (150 mg/dL) and/or HDL-C