Insulin Resistance

Dr Sudhesh Kumar MD FRCP, Professor of Medicine (Diabetes &? Metabolism), Warwick Medical School, University of Warwick Prof Steve O'Rahilly, Departments of Medicine and Clinical Biochemistry, Addenbrookes Hospital, Cambridge, UK

"The book is intended for specialists…however with the current interest in obesity and the threats it poses to the general public health, others will also find it of interest." (E-STREAMS, September 2006) "...a major contribution to the increasing body of work...this book appears at an appropriate moment to educate and excite young investigators…" (New England Journal of Medicine, November 17, 2005)

• Preface xiList of Contributors xiii1 The Insulin Receptor and Downstream Signalling 1Ken Siddle1.1 Introduction 11.2 Insulin receptor structure and function 21.3 Insulin receptor substrates 151.4 Downstream signalling pathways 231.5 The basis of insulin’s signalling specificity 371.6 Conclusion 38References 392 Insulin-mediated Regulation of Glucose Metabolism 63Daniel Konrad, Assaf Rudich and Amira Klip2.1 Introduction 632.2 Insulin as a master regulator of whole body glucose disposal 632.3 Insulin-mediated regulation of glucose metabolic pathways 672.4 Glucose uptake into skeletal muscle – the rate-limiting step in glucose metabolism 69Acknowledgements 78References 783 Insulin Action on Lipid Metabolism 87Keith N. Frayn and Fredrik Karpe3.1 Introduction: does insulin affect lipid metabolism? 873.2 Molecular mechanisms by which insulin regulates lipid metabolism 883.3 Insulin and lipolysis 893.4 Insulin, lipoprotein lipase and cellular fatty acid uptake 943.5 Co-ordinated regulation of fatty acid synthesis and ketogenesis 963.6 Insulin and cholesterol synthesis 973.7 Insulin effects on lipoprotein metabolism 98Acknowledgement 99References 994 The Effect of Insulin on Protein Metabolism 105Laura J. S. Greenlund and K. Sreekumaran Nair4.1 Introduction 1054.2 Molecular mechanisms of insulin’s effect on protein turnover 1074.3 Measurement of protein metabolism (synthesis and breakdown or turnover) in human subjects 1114.4 Whole body and regional protein turnover 114Acknowledgements 125References 1255 Genetically Modified Mouse Models of Insulin Resistance 133Gema Medina-Gomez, Christopher Lelliott and Antonio J. Vidal-Puig5.1 Introduction 1335.2 Genetic modification as a tool to dissect the mechanisms leading to insulin resistance 1345.3 Candidate genes involved in the mechanisms of insulin resistance 1345.4 Insulin signalling network 1365.5 Factors leading to insulin resistance 1375.6 Defining the function of the insulin cascade molecules through global knockouts 1375.7 Double heterozygous mice as models of polygenic forms of diabetes 1395.8 Defining tissue and/or organ relevance for the maintenance of insulin sensitivity 1405.9 Genetically modified mice to study modulators of insulin sensitivity 1425.10 Lipodystrophy versus obesity, the insulin resistance paradox 1435.11 Excess of nutrients as a cause of insulin resistance 1475.12 PPARs, key mediators of nutritional-regulated gene expression and insulin sensitivity 148References 1486 Insulin Resistance in Glucose Disposal and Production in Man with Specific Reference to Metabolic Syndrome and Type 2 Diabetes 155Henning Beck-Nielsen, Frank Alford and Ole Hother-Nielsen6.1 Introduction 1556.2 Measurement of insulin resistance 1576.3 Insulin-resistant states 1626.4 Conclusion and perspectives 171References 1727 Central Regulation of Peripheral Glucose Metabolism 179Stanley M. Hileman and Christian Bjørbæk7.1 Introduction 1797.2 Counter-regulation of hypoglycaemia – role of the CNS 1807.3 Brain regions involved in counter-regulation 1827.4 Glucosensing neurons 1847.5 Central control of peripheral organs involved in glucoregulation 1877.6 Additional afferent signals to the CNS regulating peripheral glucose metabolism 1897.7 Conclusions and future perspectives 194Acknowledgements 196References 1968 Relationship between Fat Distribution and Insulin Resistance 207Philip G. McTernan, Aresh Anwar and Sudhesh Kumar8.1 Introduction 2078.2 Fat and its distribution 2078.3 Basis for variation in adipose tissue mass 2098.4 Change in adipocyte phenotype with obesity 2108.5 Obesity and its association with insulin resistance 2108.6 Subcutaneous and visceral adipose tissue 2118.7 The pathogenic significance of abdominal adipose tissue 2118.8 Potential mechanisms linking central obesity to the metabolic syndrome 2128.9 Randle hypothesis/glucose–fatty acid hypothesis 2128.10 Alternatives to the Randle hypothesis 2138.11 Ectopic fat storage: fat content in obesity 2148.12 Adipose tissue as an endocrine organ 2148.13 Plasminogen activator–inhibitor 1 2158.14 Renin angiotensin system in adipose tissue 2168.15 Visceral obesity and steroid hormone metabolism 2178.16 Glucocorticoid metabolism and obesity 2178.17 11β-hydroxysteroid dehydrogenase (11β-HSD) 2188.18 Isoenzymes of 11β-HSD 2188.19 11β-HSD and obesity 2198.20 Sex steroid metabolism and obesity: oestrogen biosynthesis 2208.21 Aromatase 2208.22 Sex steroids and body fat 2228.23 Summary 224Acknowledgement 224References 2249 PPARγ and Glucose Homeostasis 237Robert K. Semple and Stephen O’Rahilly9.1 Evidence from cell and rodent models 2389.2 Insights from human studies 251References 25610 Adipokines and Insulin Resistance 269Daniel K. Clarke and Vidya Mohamed-Ali10.1 Obesity and insulin resistance 27010.2 Adipokines implicated in insulin resistance 27210.3 Conclusions 280References 28011 Dietary Factors and Insulin Resistance 297Jeremy Krebs and Susan Jebb11.1 Introduction 29711.2 The importance of body fatness 29811.3 Specific dietary factors 30211.4 Summary 310References 31112 Physical Activity and Insulin Resistance 317Nicholas J. Wareham, Søren Brage, Paul W. Franks and Rebecca A. Abbott12.1 Introduction 31712.2 Evidence from observational studies of the association between physical activity and insulin resistance 31812.3 Summary of findings from observational studies in adults 31812.4 Summary of findings from observational studies in children and adolescents 34012.5 Mechanisms underlying the association between physical activity and insulin resistance 35112.6 Trials of the effect of physical activity on insulin sensitivity in adults 35312.7 Trials of the effect of physical activity on insulin sensitivity in children and adolescents 37412.8 Evidence of heterogeneity of the effect of physical inactivity on insulin resistance in sub-groups of the population 37512.9 Conclusions 385References 38613 Genetics of the Metabolic Syndrome 401George Argyropoulos, Steven Smith and Claude Bouchard13.1 Historical perspective 40113.2 Pathophysiology 40413.3 Genetic epidemiology 40713.4 Monogenic disorders 41113.5 Candidate genes 41413.6 Genomic scans 42613.7 Conclusions 427References 42714 Insulin Resistance and Dyslipidaemia 451Benoît Lamarche and Jean-François Mauger14.1 Introduction 45114.2 Historical notes 45114.3 Obesity versus the insulin resistance syndrome 45314.4 Hypertriglyceridaemia 45314.5 Reduced HDL cholesterol concentrations 45514.6 Small, dense LDL particles 45714.7 LDL cholesterol levels versus LDL particle number 45914.8 Insulin resistance, dyslipidaemia and the risk of cardiovascular disease 46014.9 Conclusions 461References 46115 Insulin Resistance, Hypertension and Endothelial Dysfunction 467Stephen J. Cleland and John M. C. Connell15.1 Introduction 46715.2 Hyperinsulinaemia, insulin resistance and hypertension 46715.3 Possible mechanisms linking insulin with blood pressure 46815.4 Atherosclerosis and insulin resistance 46915.5 Vascular endothelial dysfunction and mechanisms of atherothrombotic disease 46915.6 Direct vascular action of insulin 47115.7 What causes abnormal insulin signalling in metabolic and vascular tissues? 47415.8 Summary and conclusions (Figure 15.8) 477References 47816 Insulin Resistance and Polycystic Ovary Syndrome 485Neus Potau16.1 Introduction 48516.2 Definition of polycystic ovary syndrome (PCOS) and diagnostic criteria 48616.3 Hyperandrogenism and hyperinsulinism 48916.4 Assessment of insulin resistance in PCOS 49116.5 Gene studies on PCOS 49216.6 Premature pubarche, hyperinsulinism and PCOS 49516.7 Treatment approach with antiandrogens 49716.8 Treatment approach with insulin sensitizers (metformin) 49816.9 Treatment approach with insulin sensitizers (thiazolidinediones) 50116.10 Conclusion 502References 50217 Syndromes of Severe Insulin Resistance (SSIRs) 511David Savage and Stephen O’Rahilly17.1 Introduction 51117.2 General biochemical and clinical features of severe insulin resistance 51217.3 Classification of specific syndromes of insulin resistance 51417.4 Primary disorders of insulin action 51517.5 Lipodystrophic syndromes and a lipocentric approach to diabetes 51817.6 Complex genetic syndromes associated with severe insulin resistance 52517.7 Therapeutic options in the syndromes of severe insulin resistance 526References 52718 Therapeutic Strategies for Insulin Resistance 535Harpal S. Randeva, Margaret Clarke and Sudhesh Kumar18.1 Introduction 53518.2 Obesity and insulin resistance 53518.3 Management of obesity 53718.4 Dietary management of obesity 53918.5 Exercise and physical activity 54018.6 Anti-obesity drugs 54018.7 Surgical management of obesity 54318.8 Pharmacological treatment of insulin resistance 54418.9 Insulin sensitizers and cardiovascular risk factors 55118.10 Conclusions 553References 55419 Drug Therapy for Insulin Resistance – a Look at the Future 561Bei B. Zhang and David E. Moller19.1 Introduction 56119.2 Targeting molecules within the insulin signal transduction pathway 56319.3 Targeting negative modulators of insulin signalling 56719.4 Targeting obesity and insulin resistance 569References 575Index 587