会议预告

临床文献

胰岛素抵抗(胰岛素的作用和其在疾病的干扰)

 

Editors
 
Sudhesh Kumar
 
Unit for Diabetes and Metabolism, Warwick Medical School, University of
 
Warwick, Coventry CV4 7AL, UK
 
Stephen O’Rahilly
 
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes
 
Hospital, Hill Road, Cambridge CB2 2QQ, UK
 
Preface
 
Hormone resistance syndromes are typically thought of as rare, usually genetic,disorders with a severe but relatively stereotyped clinical and biochemical profile.While there are syndromes of severe insulin resistance that conform tothis description, defective insulin action is of much more pervasive biomedicalimportance. Even moderate degrees of insulin resistance are closely linked toa range of common diseases, including Type 2 diabetes, polycystic ovary syndrome,obesity and hypertension. Not surprisingly, in recent years, there has beena tremendous increase in interest within the medical and scientific communityin understanding the causes, consequences and treatment of insulin resistance.There are several reasons for this. Firstly, we are now witnessing a revolutionin unravelling the molecular mechanism of insulin action and in understandingthe molecular basis for the various syndromes associated with insulin resistance.Secondly, we are now seeing a global epidemic of Type 2 diabetes that maypose a major threat to international public health. Thirdly, the pharmaceuticaland biotechnology industries are investing heavily in the development of newdrugs that can improve insulin action. Therefore, we believe that the publicationof this book is timely.
 
There is considerable literature available on the subject of insulin resistance. Arecent search on Medline revealed more than 20,000 articles on this subject. Thisinformation is readily accessible and one might argue that a book such as thisone might become outdated as soon as it is published! One guiding principle forthis book was, therefore, to bring to the reader not only a synthesis of importantinformation, but also the wisdom of leading researchers and clinicians who arerecognised as leaders in their own fields.
 
Each chapter stands independently and is written by one or more experts onthe subject. The book is divided into five sections with a total of 19 chapters.Section 1 reviews our current understanding of the normal biology of insulinaction and separate chapters cover insulin action in relation to glucose, lipid andprotein metabolism. Section 2 explores the pathophysiological mechanisms ofinsulin resistance, with discussion of the effects of glucose disposal in humansand in animal models. It also reviews the central regulation of energy metabolismand its perturbation, as well as the relationship between fat distribution andinsulin action and the role of the nuclear hormone receptor PPARγ in glucosemetabolism. Finally, there is a chapter discussing the role of adipose tissuesecretedproducts in causing insulin resistance. Section 3 examines the role ofgenetic and environmental factors that result in insulin resistance, including theeffects of dietary factors and physical inactivity. The genetic basis of syndromeX, a common disorder associated with insulin resistance, is described. Section 4discusses the relationship between insulin resistance and common diseases suchas dyslipidemia, hypertension and polycystic ovary syndrome. Finally, Section 5reviews the clinical management of insulin resistance, covering the many syndromesof severe insulin resistance, currently available therapeutic approachesand possible future options for drug therapy for this condition.
 
Although the book aims to provide comprehensive coverage of the subject,there are some obvious omissions, for example, the relationship between insulinresistance and Type 2 diabetes. Whilst this relationship is alluded to in manyplaces, we have not devoted a full chapter to it as there are several excellentrecent reviews on the subject.
 
The book is intended mainly for a specialist readership, although it may proveto be a useful resource for a wide variety of scientists, clinicians and postgraduatestudents with an interest in any of the related conditions. We hope that regardlessof your background as a physician, medical researcher or scientist, you willfind this book appropriate for your needs. Finally, all contributing authors haveproduced outstanding chapters that reflect their expertise and wisdom and sparedtheir valuable time despite tremendous pressures from competing obligations.We wish to thank them all for their support, hard work and friendship.
 
Sudhesh Kumar
 
Stephen O’Rahilly
 
August 2004
 
Contents
 
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
vi CONTENTS
 
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 Bj鴕b鎘
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
CONTENTS vii
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
viii CONTENTS
 
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, S鴕en 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
Beno??t Lamarche and Jean-Fran竎ois 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
CONTENTS ix
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
x CONTENTS
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
 
 
求助文献
本网站部分资源来源于网络,版权归原作者所有,转载仅作交流。如有版权问题请联系help.basalinsulin@gmail.com,我们将及时处理。
全文检索小助手:

如果您有“基础胰岛素相关文献全文”的检索需求,敬请联系help.basalinsulin@gmail.com,我们将为您搜索并发送到您的邮箱内! 请在“全文求助”邮件内尽量详细说明“标题、作者、杂志及卷期、PMID、全文链接”等内容,以便我们更精准地进行搜索!

求助全文

最新评论 暂无评论

不能超过250字,需审核,请自觉遵守互联网相关政策法规