Insulin Resistance (eBook)

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

Insulin Resistance 3
Contents 7
Preface 13
List of Contributors 15
1 The Insulin Receptor and Downstream Signalling 19
1.1 Introduction 19
1.2 Insulin receptor structure and function 20
1.3 Insulin receptor substrates 33
1.4 Downstream signalling pathways 41
1.5 The basis of insulin’s signalling specificity 55
1.6 Conclusion 56
References 57
2 Insulin-mediated Regulation of Glucose Metabolism 81
2.1 Introduction 81
2.2 Insulin as a master regulator of whole body glucose disposal 81
2.3 Insulin-mediated regulation of glucose metabolic pathways 85
2.4 Glucose uptake into skeletal muscle – the rate-limiting step in glucose metabolism 87
Acknowledgements 96
References 96
3 Insulin Action on Lipid Metabolism 105
3.1 Introduction: does insulin affect lipid metabolism? 105
3.2 Molecular mechanisms by which insulin regulates lipid metabolism 106
3.3 Insulin and lipolysis 107
3.4 Insulin, lipoprotein lipase and cellular fatty acid uptake 112
3.5 Co-ordinated regulation of fatty acid synthesis and ketogenesis 114
3.6 Insulin and cholesterol synthesis 115
3.7 Insulin effects on lipoprotein metabolism 116
Acknowledgement 117
References 117
4 The Effect of Insulin on Protein Metabolism 123
4.1 Introduction 123
4.2 Molecular mechanisms of insulin’s effect on protein turnover 125
4.3 Measurement of protein metabolism (synthesis and breakdown or turnover) in human subjects 129
4.4 Whole body and regional protein turnover 132
Acknowledgements 143
References 143
5 Genetically Modified Mouse Models of Insulin Resistance 151
5.1 Introduction 151
5.2 Genetic modification as a tool to dissect the mechanisms leading to insulin resistance 152
5.3 Candidate genes involved in the mechanisms of insulin resistance 152
5.4 Insulin signalling network 154
5.5 Factors leading to insulin resistance 155
5.6 Defining the function of the insulin cascade molecules through global knockouts 155
5.7 Double heterozygous mice as models of polygenic forms of diabetes 157
5.8 Defining tissue and/or organ relevance for the maintenance of insulin sensitivity 158
5.9 Genetically modified mice to study modulators of insulin sensitivity 160
5.10 Lipodystrophy versus obesity, the insulin resistance paradox 161
5.11 Excess of nutrients as a cause of insulin resistance 165
5.12 PPARs, key mediators of nutritional-regulated gene expression and insulin sensitivity 166
References 166
6 Insulin Resistance in Glucose Disposal and Production in Man with Specific Reference to Metabolic Syndrome and Type 2 Diabetes 173
6.1 Introduction 173
6.2 Measurement of insulin resistance 175
6.3 Insulin-resistant states 180
6.4 Conclusion and perspectives 189
References 190
7 Central Regulation of Peripheral Glucose Metabolism 197
7.1 Introduction 197
7.2 Counter-regulation of hypoglycaemia – role of the CNS 198
7.3 Brain regions involved in counter-regulation 200
7.4 Glucosensing neurons 202
7.5 Central control of peripheral organs involved in glucoregulation 205
7.6 Additional afferent signals to the CNS regulating peripheral glucose metabolism 207
7.7 Conclusions and future perspectives 212
Acknowledgements 214
References 214
8 Relationship between Fat Distribution and Insulin Resistance 225
8.1 Introduction 225
8.2 Fat and its distribution 225
8.3 Basis for variation in adipose tissue mass 227
8.4 Change in adipocyte phenotype with obesity 228
8.5 Obesity and its association with insulin resistance 228
8.6 Subcutaneous and visceral adipose tissue 229
8.7 The pathogenic significance of abdominal adipose tissue 229
8.8 Potential mechanisms linking central obesity to the metabolic syndrome 230
8.9 Randle hypothesis/glucose–fatty acid hypothesis 230
8.10 Alternatives to the Randle hypothesis 231
8.11 Ectopic fat storage: fat content in obesity 232
8.12 Adipose tissue as an endocrine organ 232
8.13 Plasminogen activator–inhibitor 1 233
8.14 Renin angiotensin system in adipose tissue 234
8.15 Visceral obesity and steroid hormone metabolism 235
8.16 Glucocorticoid metabolism and obesity 235
8.17 11?-hydroxysteroid dehydrogenase (11?-HSD) 236
8.18 Isoenzymes of 11?-HSD 236
8.19 11?-HSD and obesity 237
8.20 Sex steroid metabolism and obesity: oestrogen biosynthesis 238
8.21 Aromatase 238
8.22 Sex steroids and body fat 240
8.23 Summary 242
Acknowledgement 242
References 242
9 PPAR? and Glucose Homeostasis 255
9.1 Evidence from cell and rodent models 256
9.2 Insights from human studies 269
References 298
10 Adipokines and Insulin Resistance 287
10.1 Obesity and insulin resistance 288
10.2 Adipokines implicated in insulin resistance 290
10.3 Conclusions 298
References 298
11 Dietary Factors and Insulin Resistance 315
11.1 Introduction 315
11.2 The importance of body fatness 316
11.3 Specific dietary factors 320
11.4 Summary 328
References 329
12 Physical Activity and Insulin Resistance 335
12.1 Introduction 335
12.2 Evidence from observational studies of the association between physical activity and insulin resistance 336
12.3 Summary of findings from observational studies in adults 336
12.4 Summary of findings from observational studies in children and adolescents 358
12.5 Mechanisms underlying the association between physical activity and insulin resistance 369
12.6 Trials of the effect of physical activity on insulin sensitivity in adults 371
12.7 Trials of the effect of physical activity on insulin sensitivity in children and adolescents 392
12.8 Evidence of heterogeneity of the effect of physical inactivity on insulin resistance in sub-groups of the population 393
12.9 Conclusions 403
References 404
13 Genetics of the Metabolic Syndrome 419
13.1 Historical perspective 419
13.2 Pathophysiology 422
13.3 Genetic epidemiology 425
13.4 Monogenic disorders 429
13.5 Candidate genes 432
13.6 Genomic scans 444
13.7 Conclusions 445
References 445
14 Insulin Resistance and Dyslipidaemia 469
14.1 Introduction 469
14.2 Historical notes 469
14.3 Obesity versus the insulin resistance syndrome 471
14.4 Hypertriglyceridaemia 471
14.5 Reduced HDL cholesterol concentrations 473
14.6 Small, dense LDL particles 475
14.7 LDL cholesterol levels versus LDL particle number 477
14.8 Insulin resistance, dyslipidaemia and the risk of cardiovascular disease 478
14.9 Conclusions 479
References 479
15 Insulin Resistance, Hypertension and Endothelial Dysfunction 485
15.1 Introduction 485
15.2 Hyperinsulinaemia, insulin resistance and hypertension 485
15.3 Possible mechanisms linking insulin with blood pressure 486
15.4 Atherosclerosis and insulin resistance 487
15.5 Vascular endothelial dysfunction and mechanisms of atherothrombotic disease 487
15.6 Direct vascular action of insulin 489
15.7 What causes abnormal insulin signalling in metabolic and vascular tissues? 492
15.8 Summary and conclusions (Figure 15.8) 495
References 496
16 Insulin Resistance and Polycystic Ovary Syndrome 503
16.1 Introduction 503
16.2 Definition of polycystic ovary syndrome (PCOS) and diagnostic criteria 504
16.3 Hyperandrogenism and hyperinsulinism 507
16.4 Assessment of insulin resistance in PCOS 509
16.5 Gene studies on PCOS 510
16.6 Premature pubarche, hyperinsulinism and PCOS 513
16.7 Treatment approach with antiandrogens 515
16.8 Treatment approach with insulin sensitizers (metformin) 516
16.9 Treatment approach with insulin sensitizers (thiazolidinediones) 519
16.10 Conclusion 520
References 520
17 Syndromes of Severe Insulin Resistance (SSIRs) 529
17.1 Introduction 529
17.2 General biochemical and clinical features of severe insulin resistance 530
17.3 Classification of specific syndromes of insulin resistance 532
17.4 Primary disorders of insulin action 533
17.5 Lipodystrophic syndromes and a lipocentric approach to diabetes 536
17.6 Complex genetic syndromes associated with severe insulin resistance 543
17.7 Therapeutic options in the syndromes of severe insulin resistance 544
References 545
18 Therapeutic Strategies for Insulin Resistance 553
18.1 Introduction 553
18.2 Obesity and insulin resistance 553
18.3 Management of obesity 555
18.4 Dietary management of obesity 557
18.5 Exercise and physical activity 558
18.6 Anti-obesity drugs 558
18.7 Surgical management of obesity 561
18.8 Pharmacological treatment of insulin resistance 562
18.9 Insulin sensitizers and cardiovascular risk factors 569
18.10 Conclusions 571
References 572
19 Drug Therapy for Insulin Resistance – a Look at the Future 579
19.1 Introduction 579
19.2 Targeting molecules within the insulin signal transduction pathway 581
19.3 Targeting negative modulators of insulin signalling 585
19.4 Targeting obesity and insulin resistance 587
References 593
Index 605

"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)