Insulin Resistance

Diabetes is now one of the major causes of morbidity worldwide. In many cases, the onset of diabetes is progressive, developing via a condition of insulin resistance. This book considers the development of this condition, its consequences and clinical and therapeutic aspects. The book reviews the normal biology of insulin action on glucose, lipids and proteins. It considers the pathological basis for insulin resistance in animal models and humans, and discusses the influence of heredity, dietary factors and exercise. Clinical consequences including dyslipidaemia, hypertension and polycystic ovary syndrome, and therapeutic strategies for treatment are also examined. * Provides an expert review of the phenomenon of insulin resistance * Brings together a host of recent research for the first time * Written by leading experts in biological and clinical research

Preface xi List of Contributors xiii 1 The Insulin Receptor and Downstream Signalling 1 Ken Siddle 1.1 Introduction 1 1.2 Insulin receptor structure and function 2 1.3 Insulin receptor substrates 15 1.4 Downstream signalling pathways 23 1.5 The basis of insulin’s signalling specificity 37 1.6 Conclusion 38 References 39 2 Insulin-mediated Regulation of Glucose Metabolism 63 Daniel Konrad, Assaf Rudich and Amira Klip 2.1 Introduction 63 2.2 Insulin as a master regulator of whole body glucose disposal 63 2.3 Insulin-mediated regulation of glucose metabolic pathways 67 2.4 Glucose uptake into skeletal muscle – the rate-limiting step in glucose metabolism 69 Acknowledgements 78 References 78 3 Insulin Action on Lipid Metabolism 87 Keith N. Frayn and Fredrik Karpe 3.1 Introduction: does insulin affect lipid metabolism? 87 3.2 Molecular mechanisms by which insulin regulates lipid metabolism 88 3.3 Insulin and lipolysis 89 3.4 Insulin, lipoprotein lipase and cellular fatty acid uptake 94 3.5 Co-ordinated regulation of fatty acid synthesis and ketogenesis 96 3.6 Insulin and cholesterol synthesis 97 3.7 Insulin effects on lipoprotein metabolism 98 Acknowledgement 99 References 99 4 The Effect of Insulin on Protein Metabolism 105 Laura J. S. Greenlund and K. Sreekumaran Nair 4.1 Introduction 105 4.2 Molecular mechanisms of insulin’s effect on protein turnover 107 4.3 Measurement of protein metabolism (synthesis and breakdown or turnover) in human subjects 111 4.4 Whole body and regional protein turnover 114 Acknowledgements 125 References 125 5 Genetically Modified Mouse Models of Insulin Resistance 133 Gema Medina-Gomez, Christopher Lelliott and Antonio J. Vidal-Puig 5.1 Introduction 133 5.2 Genetic modification as a tool to dissect the mechanisms leading to insulin resistance 134 5.3 Candidate genes involved in the mechanisms of insulin resistance 134 5.4 Insulin signalling network 136 5.5 Factors leading to insulin resistance 137 5.6 Defining the function of the insulin cascade molecules through global knockouts 137 5.7 Double heterozygous mice as models of polygenic forms of diabetes 139 5.8 Defining tissue and/or organ relevance for the maintenance of insulin sensitivity 140 5.9 Genetically modified mice to study modulators of insulin sensitivity 142 5.10 Lipodystrophy versus obesity, the insulin resistance paradox 143 5.11 Excess of nutrients as a cause of insulin resistance 147 5.12 PPARs, key mediators of nutritional-regulated gene expression and insulin sensitivity 148 References 148 6 Insulin Resistance in Glucose Disposal and Production in Man with Specific Reference to Metabolic Syndrome and Type 2 Diabetes 155 Henning Beck-Nielsen, Frank Alford and Ole Hother-Nielsen 6.1 Introduction 155 6.2 Measurement of insulin resistance 157 6.3 Insulin-resistant states 162 6.4 Conclusion and perspectives 171 References 172 7 Central Regulation of Peripheral Glucose Metabolism 179 Stanley M. Hileman and Christian Bjørbæk 7.1 Introduction 179 7.2 Counter-regulation of hypoglycaemia – role of the CNS 180 7.3 Brain regions involved in counter-regulation 182 7.4 Glucosensing neurons 184 7.5 Central control of peripheral organs involved in glucoregulation 187 7.6 Additional afferent signals to the CNS regulating peripheral glucose metabolism 189 7.7 Conclusions and future perspectives 194 Acknowledgements 196 References 196 8 Relationship between Fat Distribution and Insulin Resistance 207 Philip G. McTernan, Aresh Anwar and Sudhesh Kumar 8.1 Introduction 207 8.2 Fat and its distribution 207 8.3 Basis for variation in adipose tissue mass 209 8.4 Change in adipocyte phenotype with obesity 210 8.5 Obesity and its association with insulin resistance 210 8.6 Subcutaneous and visceral adipose tissue 211 8.7 The pathogenic significance of abdominal adipose tissue 211 8.8 Potential mechanisms linking central obesity to the metabolic syndrome 212 8.9 Randle hypothesis/glucose–fatty acid hypothesis 212 8.10 Alternatives to the Randle hypothesis 213 8.11 Ectopic fat storage: fat content in obesity 214 8.12 Adipose tissue as an endocrine organ 214 8.13 Plasminogen activator–inhibitor 1 215 8.14 Renin angiotensin system in adipose tissue 216 8.15 Visceral obesity and steroid hormone metabolism 217 8.16 Glucocorticoid metabolism and obesity 217 8.17 11β-hydroxysteroid dehydrogenase (11β-HSD) 218 8.18 Isoenzymes of 11β-HSD 218 8.19 11β-HSD and obesity 219 8.20 Sex steroid metabolism and obesity: oestrogen biosynthesis 220 8.21 Aromatase 220 8.22 Sex steroids and body fat 222 8.23 Summary 224 Acknowledgement 224 References 224 9 PPARγ and Glucose Homeostasis 237 Robert K. Semple and Stephen O’Rahilly 9.1 Evidence from cell and rodent models 238 9.2 Insights from human studies 251 References 256 10 Adipokines and Insulin Resistance 269 Daniel K. Clarke and Vidya Mohamed-Ali 10.1 Obesity and insulin resistance 270 10.2 Adipokines implicated in insulin resistance 272 10.3 Conclusions 280 References 280 11 Dietary Factors and Insulin Resistance 297 Jeremy Krebs and Susan Jebb 11.1 Introduction 297 11.2 The importance of body fatness 298 11.3 Specific dietary factors 302 11.4 Summary 310 References 311 12 Physical Activity and Insulin Resistance 317 Nicholas J. Wareham, Søren Brage, Paul W. Franks and Rebecca A. Abbott 12.1 Introduction 317 12.2 Evidence from observational studies of the association between physical activity and insulin resistance 318 12.3 Summary of findings from observational studies in adults 318 12.4 Summary of findings from observational studies in children and adolescents 340 12.5 Mechanisms underlying the association between physical activity and insulin resistance 351 12.6 Trials of the effect of physical activity on insulin sensitivity in adults 353 12.7 Trials of the effect of physical activity on insulin sensitivity in children and adolescents 374 12.8 Evidence of heterogeneity of the effect of physical inactivity on insulin resistance in sub-groups of the population 375 12.9 Conclusions 385 References 386 13 Genetics of the Metabolic Syndrome 401 George Argyropoulos, Steven Smith and Claude Bouchard 13.1 Historical perspective 401 13.2 Pathophysiology 404 13.3 Genetic epidemiology 407 13.4 Monogenic disorders 411 13.5 Candidate genes 414 13.6 Genomic scans 426 13.7 Conclusions 427 References 427 14 Insulin Resistance and Dyslipidaemia 451 Benoît Lamarche and Jean-François Mauger 14.1 Introduction 451 14.2 Historical notes 451 14.3 Obesity versus the insulin resistance syndrome 453 14.4 Hypertriglyceridaemia 453 14.5 Reduced HDL cholesterol concentrations 455 14.6 Small, dense LDL particles 457 14.7 LDL cholesterol levels versus LDL particle number 459 14.8 Insulin resistance, dyslipidaemia and the risk of cardiovascular disease 460 14.9 Conclusions 461 References 461 15 Insulin Resistance, Hypertension and Endothelial Dysfunction 467 Stephen J. Cleland and John M. C. Connell 15.1 Introduction 467 15.2 Hyperinsulinaemia, insulin resistance and hypertension 467 15.3 Possible mechanisms linking insulin with blood pressure 468 15.4 Atherosclerosis and insulin resistance 469 15.5 Vascular endothelial dysfunction and mechanisms of atherothrombotic disease 469 15.6 Direct vascular action of insulin 471 15.7 What causes abnormal insulin signalling in metabolic and vascular tissues? 474 15.8 Summary and conclusions (Figure 15.8) 477 References 478 16 Insulin Resistance and Polycystic Ovary Syndrome 485 Neus Potau 16.1 Introduction 485 16.2 Definition of polycystic ovary syndrome (PCOS) and diagnostic criteria 486 16.3 Hyperandrogenism and hyperinsulinism 489 16.4 Assessment of insulin resistance in PCOS 491 16.5 Gene studies on PCOS 492 16.6 Premature pubarche, hyperinsulinism and PCOS 495 16.7 Treatment approach with antiandrogens 497 16.8 Treatment approach with insulin sensitizers (metformin) 498 16.9 Treatment approach with insulin sensitizers (thiazolidinediones) 501 16.10 Conclusion 502 References 502 17 Syndromes of Severe Insulin Resistance (SSIRs) 511 David Savage and Stephen O’Rahilly 17.1 Introduction 511 17.2 General biochemical and clinical features of severe insulin resistance 512 17.3 Classification of specific syndromes of insulin resistance 514 17.4 Primary disorders of insulin action 515 17.5 Lipodystrophic syndromes and a lipocentric approach to diabetes 518 17.6 Complex genetic syndromes associated with severe insulin resistance 525 17.7 Therapeutic options in the syndromes of severe insulin resistance 526 References 527 18 Therapeutic Strategies for Insulin Resistance 535 Harpal S. Randeva, Margaret Clarke and Sudhesh Kumar 18.1 Introduction 535 18.2 Obesity and insulin resistance 535 18.3 Management of obesity 537 18.4 Dietary management of obesity 539 18.5 Exercise and physical activity 540 18.6 Anti-obesity drugs 540 18.7 Surgical management of obesity 543 18.8 Pharmacological treatment of insulin resistance 544 18.9 Insulin sensitizers and cardiovascular risk factors 551 18.10 Conclusions 553 References 554 19 Drug Therapy for Insulin Resistance – a Look at the Future 561 Bei B. Zhang and David E. Moller 19.1 Introduction 561 19.2 Targeting molecules within the insulin signal transduction pathway 563 19.3 Targeting negative modulators of insulin signalling 567 19.4 Targeting obesity and insulin resistance 569 References 575 Index 587