The Metabolic Syndrome:: Epidemiology, Clinical Treatment, and Underlying Mechanisms (Contemporary Endocrinology)

The Metabolic Syndrome: Epidemiology, Clinical Treatment, and Underlying Mechanisms (Contemporary Endocrinology)......Page 1 Front-matter......Page 2 Title Page ......Page 4 Copyright Page ......Page 5 PREFACE......Page 6 REFERENCES......Page 7 Table of Contents (with page links in titles & page numbers)......Page 8 CONTRIBUTORS......Page 10 COLOR PLATES......Page 12 BACKGROUND......Page 14 NATURAL HISTORY......Page 15 CHAPTER SUMMARIES......Page 16 REFERENCES......Page 18 I. Epidemilogy And Clinical Treatment: Issues In Defining And Treating The Metabolic Syndrome......Page 21 INTRODUCTION......Page 22 IT'S A BIRD! IT'S A PlANE! IT'S THE METABOLIC SYNDROME!......Page 23 WHAT IS THE RELATIONSHIP AMONG THE METABOLIC SYNDROME DIAGNOSTIC CRITERIA: CASUAL OR CAUSAL? ......Page 26 Dyslipidemia......Page 27 POSTPRANDIAL LIPEMIA......Page 28 ATHEROGENIC LIPOPROTEINS AND INSULIN RESISTANCE......Page 29 Blood Pressure......Page 30 Insulin Resistance and Procoagulant and Proinflammatory Factors......Page 31 Obesity and Insulin-Mediated Glucose Uptake (IMGU)......Page 32 WC versus BMI as Predictors of IMGU ......Page 33 Relationship Among Adiposity, Insulin Resistance, and CVD Risk......Page 34 INTERACTION AMONG BMI, INSULIN ACTION, AND CVD RISK FACTORS......Page 35 OBESITY DOES NOT NECESSARILY TRANSLATE INTO INCREASED CVD RISK......Page 36 Visceral Obesity and Insulin Resistance......Page 37 Visceral Fat and Adverse Clinical Outcomes......Page 39 IS THERE CLINICAL UTILITY IN DIAGNOSING THE METS?......Page 40 REFERENCES......Page 42 OVERVIEW......Page 48 METABOLIC SYNDROME AND OBESITY......Page 49 THE ROLE OF OBESITY IN RISK FACTOR CLUSTERING AND METABOLIC SYNDROME ......Page 50 MECHANISMS FOR RISK FACTOR CLUSTERING ASSOCIATED WITH OBESITY ......Page 51 TREATMENT OPTIONS TO REDUCE RISK FACTOR CLUSTERING ASSOCIATED WITH OBESITY ......Page 55 REFERENCES......Page 57 INTRODUCTION......Page 67 Effects of Weight Loss on Central Adiposity......Page 68 Exercise and Loss of Body Weight and Visceral Fat......Page 69 RIMONABANT......Page 71 ORLISTAT......Page 73 SIBUTRAMINE......Page 74 LAPAROSCOPIC PLACEMENT OF A GASTRIC BAND......Page 76 LIPOSUCTION AND OMENTECTOMY......Page 77 Testosterone and Anabolic Steroids......Page 78 CONCLUSION......Page 79 REFERENCES......Page 80 INSULIN RESISTANCE AND SURROGATE MEASURES FOR INSULIN RESISTANCE ......Page 84 THE METABOLIC SYNDROME AND CARDIOVASCULAR DISEASE......Page 87 MECHANISMS......Page 88 REFERENCES......Page 89 6 The Sympatho-Adrenal System in the Metabolic Syndrome ......Page 94 SYMPATHETIC NERVOUS SYSTEM (SNS) ACTIVITY IS INCREASED IN THE METABOLIC SYNDROME ......Page 95 Insulin Stimulates the SNS......Page 96 LEPTIN STIMULATES SNS ACTIVITY......Page 97 Insulin Mediates Dietary Changes in SNS Activity......Page 98 THE ADAPTIVE SIGNIFICANCE OF INSULIN RESISTANCE......Page 99 Insulin Resistance as a Compensatory Mechanism......Page 100 INCREASED SYMPATHETIC ACTIVITY IN OBESITY DEPENDS ON INSULIN AND IS LINKED TO BLOOD PRESSURE ......Page 101 CAN INCREASED SNS ACTIVITY BE THE PRIMARY ABNORMALITY IN THE METABOLIC SYNDROME? ......Page 102 Evidence Against a Primary Role for the SNS......Page 103 Low Levels of Epinephrine Are Related to High Triglyceride and Low HDL-Cholesterol Levels ......Page 104 SLEEP DEBT Is ASSOCIATED WITH INCREASED CORTISOL LEVELS AND INSULIN RESISTANCE ......Page 106 DIETARY RECOMMENDATIONS......Page 107 CONCLUSIONS: FEAST OR FAMINE-THE LEGACY OF THRIFTY METABOLIC TRAITS IN THE FACE OF AN ABUNDANT FOOD SUPPLY ......Page 108 REFERENCES......Page 109 II. Endothelial Function, Inflammation, and Dyslipidemia......Page 114 INTRODUCTION......Page 115 INSULIN RECEPTOR TYROSINE KINASE......Page 116 PHOSPHATIDYLINOSITOL 3-KINASE......Page 117 CHARACTERISTIC FEATURES OF ENOS ACTIVATION IN RESPONSE TO INSULIN......Page 118 Insulin-Stimulated Secretion of ET-1 ......Page 119 Insulin and Nitric Oxide-Dependent Vasodilation......Page 120 PARALLEL INSULIN SIGNALING PATHWAYS IN METABOLIC AND VASCULAR TISSUES ......Page 123 Integrated Actions of Insulin in Skeletal Muscle Beds......Page 124 Insulin Resistance Couples Vascular and Metabolic Pathophysiology......Page 125 GENERALIZED VASCULAR DYSFUNCTION IN INSULIN RESISTANCE ......Page 126 Insulin and Endothelin Action in the Vasculature......Page 129 Pharmacological Therapies Targeting Insulin Resistance......Page 132 Pharmacological Therapies Targeting Endothelial Dysfunction......Page 133 REFERENCES......Page 135 INTRODUCTION......Page 144 The cp (Corpulent) Gene......Page 145 The fa (Fatty) Gene......Page 146 MACROVASCULAR DISEASE......Page 147 Thrombosis......Page 148 Vasculopathy......Page 149 Vascular Smooth Muscle Cells......Page 152 Insulin Resistance......Page 154 Hyperlipdemia......Page 156 Cytokines and Vascular Disease Risk......Page 157 HORMONAL STATUS AND POLYCYSTIC OVARY DISEASE......Page 158 INTERVENTIONS......Page 160 α-Glucosidase Inhibitors ......Page 161 Dietary Components and Supplements......Page 162 Anorectic/Insulin-Sensitizing Pharmaceutical Agents......Page 164 Nitric Oxide Metabolism......Page 165 Calcium Channel Antagonists......Page 166 Environmental Stress and Toxic Agents......Page 167 REFERENCES......Page 168 ABSTRACT......Page 174 C-REACTIVE PROTEIN (CRP): BIOLOGICAL PROPERTIES AND CLINICAL USE ......Page 175 CRP and Obesity......Page 176 CRP and Glucose Homeostasis......Page 179 CRP and Hypertension......Page 180 CRP and Lipid Metabolism......Page 181 CRP AND THE PREVALENCE AND INCIDENCE OF METABOLIC SYNDROME: EPIDEMIOLOGICAL EVIDENCE ......Page 182 COMPARISON OF THE PREDICTIVE VALUES OF CRP AND THE METABOLIC SYNDROME ON CARDIOVASCULAR AND DIABETES RISK ......Page 186 IMPLICATIONS AND FUTURE RESEARCH......Page 187 REFERENCES......Page 189 FIRST-DEGREE RELATIVES OF TYPE 2 DIABETIC PATIENTS AND RISK OF DIABETES ......Page 196 Evidence of Dysregulated Adipose Tissue in First-Degree Relatives and Insulin Resistance ......Page 197 Insulin Signaling Leading to Glucose Uptake and Other Effects in Adipose Cells ......Page 198 Adipose Tissue Is Dysregulated in Insulin Resistance and Type 2 Diabetes Effectson Insulin Signaling and Adipocyte Function ......Page 200 ADIPOSE TISSUE AND INFLAMMATION......Page 201 Inflammatory Markers CRP and SAA ......Page 203 THIAZOLIDINEDIONES......Page 204 REFERENCES......Page 205 EPIDEMIOLOGY OF DYSLIPIDEMIA AND INSULIN RESISTANCE......Page 212 NORMAL LIPID AND LIPOPROTEIN PHYSIOLOGY......Page 213 Overproduction of VLDL......Page 217 Defective VWL, Remnant, and LDL Catabolism......Page 218 Generation of Small, DenseWL......Page 219 Increased Catabolism of HDL ......Page 220 Postprandial Hyperlipidemia......Page 221 SUMMARY......Page 222 REFERENCES......Page 223 III. Insulin—Secretion and Action: Underlying Mechanisms of the Metabolic Syndrome......Page 226 OBESITY AND PANCREATIC FAT......Page 227 OBESITY AND PANCREATIC ISLET FUNCTION......Page 229 Effects of Sustained Hyperlipidemia on Insulin Secretion......Page 230 Beta Cell Lipoapoptosis and the Role of Saturated NEFAs......Page 231 LIPIDS, INSULIN RESISTANCE, AND ISLET AMYLOID FORMATION......Page 232 REFERENCES......Page 234 ABSTRACT......Page 239 GLUCAGON-LIKE PEPTIDES......Page 240 EXPRESSION OF THE GLUCAGON GENE......Page 241 EXPRESSION OF THE RECEPTORS FOR THE GLUCAGON-LIKE PEPTIDES ......Page 243 Effects on the Islets......Page 244 Effects on the Gastrointestinal Tract......Page 245 Other Actions......Page 246 ACTIONS OF GLP-2......Page 247 EFFECTS OF GLP-I ON INSULIN ACTION......Page 248 Therapeutic Application of Proglucagon-Derived Peptides ......Page 251 REFERENCES......Page 252 INTRODUCTION......Page 261 THE MAMMALIAN INSULIN/IGF1 RECEPTOR TYROSINE KINASES ......Page 262 INSULIN/IGF SIGNALING: THE BASICS......Page 263 IRS2 SIGNALING REVEALS THE LINK BETWEEN PERIPHERAL INSULIN ACTION AND PANCREATIC ß-CELL FUNCTION ......Page 265 INSULIN SIGNALING IN HEPATIC METABOLISM......Page 269 Introduction......Page 271 Multisite SIT-Phosphorylation of IRS-Proteins......Page 272 IRS-PROTEIN DEGRADATION......Page 273 THE RELATION BETWEEN GLP1 AND IRS2 SIGNALING ......Page 274 SUMMARY AND PERSPECTIVE......Page 275 REFERENCES......Page 276 INSULIN RESISTANCE......Page 284 INSULIN SIGNALING PATHWAY......Page 285 THE INSULIN RECEPTOR......Page 287 Functional Aspects of IR Structure......Page 288 STRUCTURAL ASPECTS OF IR AUTOPHOSPHORYLATION......Page 289 FUNCTIONAL ASPECTS OF IR TYROSINE KINASE ACTIVITY......Page 290 INSULIN RECEPTOR FUNCTION IN INSULIN RESISTANCE......Page 292 Diet......Page 293 Inherited Insulin Resistance......Page 294 Pregnancy......Page 295 TYROSINE PHOSPHATASES......Page 296 PC-1 ......Page 297 PROTEIN KINASE C-MEDIATED SERINE PHOSPHORYLATION......Page 299 CYTOKINE ACTIVATED SERINE KINASES......Page 301 REFERENCES......Page 302 INTRODUCTION......Page 311 OVERVIEW OF LIPID METABOLISM AND INSULIN RESISTANCE......Page 312 ACUTE FATTY ACID ELEVATION CAN CAUSE MUSCLE INSULIN RESISTANCE ......Page 313 Animal Studies......Page 314 Human Studies......Page 315 Long-Chain Acyl CoAs......Page 316 DAGs and Ceramides......Page 317 Muscle Membrane Composition......Page 318 ADIPOSE BODY DEPOTS AND FFA FLUXES TO MUSCLE......Page 319 CYfOKINES AND INFLAMMATORY PATHWAYS: AN ADDITIONAL COMPONENT OF MUSCLE INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES ......Page 320 PHARMACOLOGICAL MANIPULATION OF MUSCLE LIPID ACCUMULATION ......Page 321 PPARγ Agonists ......Page 322 PPARα Agonists ......Page 323 REFERENCES......Page 324 INTRODUCTORY OVERVIEW......Page 333 GENERAL ASPECTS OF INSULIN SIGNALING......Page 334 TISSUE-SPECIFIC DIFFERENCES IN UPSTREAM ACTIVATORS OF aPKC AND PKB......Page 336 INSULIN SIGNALING DEFECTS IN MUSCLE AND ADIPOSE TISSUE IN TYPE 2 DIABETES ......Page 337 INSULIN SIGNALING DEFECTS IN MUSCLE IN OBESITY......Page 338 INSULIN SIGNALING IN LIVERS OF DIABETIC RODENTS......Page 339 METABOLIC CONSEQUENCES OF DIVERGENT ALTERATIONS OF INSULIN SIGNALING IN MUSCLE AND LIVER IN OBESITY AND DIABETES ......Page 340 Exercise......Page 341 Thiazolidinediones......Page 342 REFERENCES......Page 343 INTRODUCTION......Page 347 THE BIOLOGY OF DIABETES: FOCUS ON HYPERGLYCEMIA......Page 348 Pathophysiology......Page 349 Glucose Levels and Fluxes......Page 350 Free Fatty Acids and Hormones......Page 352 Postprandial Suppression of Endogenous Glucose Production in Normal Controls and Type 2 Diabetic Subjects ......Page 353 HEPATIC INSULIN ACTION AND THE METABOLIC MACHINERY UNDERLYING GLUCOSE METABOLISM IN THE LIVER ......Page 356 Glucogenic Metabolite Fluxes: Glycogenic Substrates and Signals......Page 357 Links Between Gluconeogenesis and Hepatic Glycogen in Type 2 Diabetes......Page 358 GLUCOSE PRODUCTION......Page 359 GLUCOSE UPTAKE......Page 360 GLUCOSE-LIPID INTERACTIONS, REGULATION BY INSULIN, AND TYPE 2 DIABETES ......Page 361 Metabolic Zonation: The Effects of O2 and Nonalcoholic Steatohepatitis ......Page 362 Theoretical Approaches......Page 363 REFERENCES......Page 365 A LONG LOOK BACK......Page 380 KEY FEATURES OF THE METABOLIC SYNDROME: A REDUCTIONIST APPROACH FOR THE EPIDEMIOLOGIST OR FOR THE CLINICAL PRACTITIONER ......Page 381 THE COMPLEXITY OF THE METABOLIC SYNDROME: PATTERN RECOGNITION ......Page 384 THE LONGITUDINAL DEVELOPMENT OF THE METABOLIC SYNDROME ......Page 386 REFERENCES......Page 390 INDEX......Page 394 The Writers Stimulate New Thinking Concerning Underlying Mechanisms And Encourage Heightened Efforts To Develop New Therapeutics, Potentially Targeting Uniquely Intersecting Pathways. Developing This New Synthesis And Analysis Of The Metabolic Syndrome Will Bring Together The Viewpoints Of Epidemiologists, Physiologists, Molecular Biologists/biochemists, And Clinicians Toward Understanding The Current State Of Knowledge Of Both The Causes And Consequences Of The Metabolic Syndrome. Metabolic Syndrome -- Past And Future: An Introduction To The Features Of This Book -- Metabolic Syndrome: To Be Or Not To Be? -- The Role Of Obesity In Insulin Resistance: Epidemiological And Metabolic Aspects -- Treatment Of The Metabolic Syndrome With Weight Loss, Exercise, Hormones, And Surgery -- Insulin Resistance, Metabolic Syndrome, And Cardiovascular Disease: An Epidemiological Perspective -- The Sympatho-adrenal System In The Metabolic Syndrome -- Insulin Action And Endothelial Function -- Macro- And Microvascular Disease In An Insulin-resistant Pre-diabetic Animal Model: The Jcr:la-cp Rat -- High-sensitivity C-reactive Protein And The Metabolic Syndrome -- Insulin Signaling In Adipocytes And The Role Of Inflammation -- Insulin Resistance And Dyslipidemia -- Pancreatic Islet Pathophysiology And Pathology In Obesity -- Glucagon-like Peptides And Insulin Sensitivity -- The Relationship Between The Insulin Receptor Substrates And Metabolic Disease -- Insulin Resistance And Inhibitors Of The Insulin Receptor Tyrosine Kinase -- Fat Feeding And Muscle Fat Deposition Eliciting Insulin Resistance: An Update -- Alterations In Atypical Protein Kinase C Activation In Insulin Resistance Syndromes -- The Liver, Glucose Homeostasis, And Insulin Action In Type 2 Diabetes Mellitus -- Chronomics Of The Metabolic Syndrome. Edited By Barbara Caleen Hansen And George A. Bray. Includes Bibliographical References And Index. In the United States, 40 to 45% of those over 60 years of age have the metabolic syndrome (1,2,3), and this percentage, based on estimates of the increasing prevalence ofexcess body weight and the more comprehensive diagnostic criteria for the syndrome, is likely to exceed 60% in newer survey analyses. Children and adolescents, too, are being affected by the metabolic syndrome, in parallel with the increasing prevalence of overweight in young people, now estimated to include 16% of those age 6 to 19 years. Clinicians see with increasing frequency that routine office visits demonstrate the meta­ bolic syndrome, a constellation of discrete but closely related metabolic disturbances indicative of increased risk for (or presence of) cardiovascular disease and/or diabetes. All estimates suggest the increasing impactof the metabolic syndrome on mortality and morbidity (4). Our aim in developing this new synthesis and analysis of the metabolic syndrome has been to bring together the viewpoints of the epidemiologists, the physiologists, the molecular biologists/biochemists, and the clinicians toward understanding the current state ofknowledge ofboth the causes and the consequences of the metabolic syndrome. These writers aim to stimulate new thinking concerning underlying mechanisms and to encourage heightened efforts to develop new therapeutics, potentially targeting uniquely intersecting pathways or points of intervention. This book is an extended call to action to slow or halt the rising tide of the metabolic syndrome (5). With an extraordinary need for early intervention and prevention to slow or halt its progression, Metabolic Syndrome is one of the most challenging health problems. Only through an understanding of the science underlying this syndrome can successful interventions be developed and implemented. In The Metabolic Syndrome: Epidemiology, Clinical Treatment, and Underlying Mechanisms, the writers stimulate new thinking concerning underlying mechanisms and encourage heightened efforts to develop new therapeutics, potentially targeting uniquely intersecting pathways. Developing this new synthesis and analysis of the Metabolic Syndrome will bring together the viewpoints of epidemiologists, physiologists, molecular biologists/biochemists, and clinicians toward understanding the current state of knowledge of both the causes and consequences of the Metabolic Syndrome