Insulin Resistance: Insulin Action and Its Disturbances in Disease

603 Pages·2004·4.85 MB·English

Insulin Resistance
Insulin Resistance : Insulin Action and Its Disturbances in Disease . Edited by Sudhesh Kumar and Stephen O’Rahilly
 2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6
Insulin Resistance
Insulin Action and Its Disturbances in Disease
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
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Insulinresistance:insulinactionanditsdisturbancesindisease/editors,Sudhesh
Kumar,StephenO’Rahilly.
p.cm.
Includesbibliographicalreferencesandindex.
ISBN0-470-85008-6
1.Insulinresistance.I.Kumar,Sudhesh.II.O’Rahilly,S.(Stephen)
RC662.4.I5562004
616.4(cid:1)6207–dc22
2004016888
BritishLibraryCataloguinginPublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
ISBN0-470-85008-6
Typesetin10.5/13ptTimesbyLaserwordsPrivateLimited,Chennai,India
PrintedandboundinGermany
Thisbookisprintedonacid-freepaperresponsiblymanufacturedfromsustainableforestry
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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 structureand function 2
1.3 Insulin receptor substrates 15
1.4 Downstream signalling pathways 23
1.5 The basis of insulin’ssignallingspecificity 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 glucosemetabolic 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 insulinregulates lipid metabolism 88
3.3 Insulin and lipolysis 89
3.4 Insulin, lipoproteinlipase and cellular fatty acid uptake 94
3.5 Co-ordinated regulation of fatty acid synthesisand ketogenesis 96
3.6 Insulin and cholesterol synthesis 97
3.7 Insulin effects on lipoproteinmetabolism 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 (synthesisand 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 insulinresistance 134
5.4 Insulin signallingnetwork 136
5.5 Factors leading to insulin resistance 137
5.6 Defining the function of the insulincascade molecules through global
knockouts 137
5.7 Doubleheterozygous mice as models of polygenicforms of diabetes 139
5.8 Defining tissueand/or organ relevance for themaintenance of insulin
sensitivity 140
5.9 Genetically modified mice to study modulators of insulinsensitivity 142
5.10 Lipodystrophyversus obesity, the insulinresistance paradox 143
5.11 Excess of nutrients as a cause of insulinresistance 147
5.12 PPARs, key mediators of nutritional-regulatedgene 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-resistantstates 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 Glucosensingneurons 184
CONTENTS vii
7.5 Central control of peripheral organs involved in glucoregulation 187
7.6 Additional afferent signalsto 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 adiposetissuemass 209
8.4 Change in adipocytephenotypewith obesity 210
8.5 Obesity and its association with insulinresistance 210
8.6 Subcutaneous and visceral adiposetissue 211
8.7 The pathogenic significanceof abdominal adipose tissue 211
8.8 Potential mechanisms linking central obesity to themetabolic syndrome 212
8.9 Randle hypothesis/glucose–fattyacid hypothesis 212
8.10 Alternatives to the Randle hypothesis 213
8.11 Ectopic fat storage: fat content in obesity 214
8.12 Adipose tissueas an endocrine organ 214
8.13 Plasminogen activator–inhibitor1 215
8.14 Renin angiotensinsystem in adiposetissue 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, Søren Brage, Paul W. Franks and
Rebecca A. Abbott
12.1 Introduction 317
12.2 Evidence from observationalstudies of the association between physical
activity and insulinresistance 318
12.3 Summary of findings from observationalstudies in adults 318
12.4 Summary of findings from observationalstudies in children and adolescents 340
12.5 Mechanisms underlyingthe association between physical activity and insulin
resistance 351
12.6 Trials of the effect of physical activity on insulin sensitivityin adults 353
12.7 Trials of the effect of physical activity on insulin sensitivityin children and
adolescents 374
12.8 Evidence of heterogeneity of the effect of physical inactivity on insulin
resistance in sub-groupsof 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 Monogenicdisorders 411
13.5 Candidate genes 414
13.6 Genomic scans 426
13.7 Conclusions 427
References 427
14 Insulin Resistance and Dyslipidaemia 451
Benoˆıt Lamarche and Jean-Franc¸ois Mauger
14.1 Introduction 451
14.2 Historical notes 451
14.3 Obesity versus the insulinresistance 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, dyslipidaemiaand 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, insulinresistance and hypertension 467
15.3 Possible mechanisms linking insulinwith blood pressure 468
15.4 Atherosclerosis and insulin resistance 469
15.5 Vascularendothelialdysfunctionandmechanismsofatherothromboticdisease 469
15.6 Direct vascular action of insulin 471
15.7 What causes abnormal insulinsignallingin 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 polycysticovary syndrome (PCOS) and diagnosticcriteria 486
16.3 Hyperandrogenism and hyperinsulinism 489
16.4 Assessment of insulinresistance in PCOS 491
16.5 Gene studies on PCOS 492
16.6 Premature pubarche, hyperinsulinismand PCOS 495
16.7 Treatment approach with antiandrogens 497
16.8 Treatment approach with insulinsensitizers (metformin) 498
16.9 Treatment approach with insulinsensitizers (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 insulinresistance 512
17.3 Classification of specific syndromes of insulin resistance 514
17.4 Primary disorders of insulinaction 515
17.5 Lipodystrophicsyndromes and a lipocentricapproach to diabetes 518
17.6 Complex genetic syndromes associated with severe insulin resistance 525
17.7 Therapeutic options in the syndromes of severe insulinresistance 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-obesitydrugs 540
18.7 Surgical management of obesity 543
18.8 Pharmacological treatment of insulinresistance 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 insulinsignal transduction pathway 563
19.3 Targeting negativemodulators of insulinsignalling 567
19.4 Targeting obesity and insulinresistance 569
References 575
Index 587
Preface
Hormone resistance syndromes are typically thought of as rare, usually genetic,
disorders with a severe but relatively stereotyped clinical and biochemical pro-
file. While there are syndromes of severe insulin resistance that conform to
this description, defective insulin action is of much more pervasive biomedical
importance. Even moderate degrees of insulin resistance are closely linked to
a range of common diseases, including Type 2 diabetes, polycystic ovary syn-
drome,obesityandhypertension.Notsurprisingly,inrecentyears,therehasbeen
a tremendous increase in interest within the medical and scientific community
in understanding the causes, consequences and treatment of insulin resistance.
There are several reasons for this. Firstly, we are now witnessing a revolution
in unravelling the molecular mechanism of insulin action and in understanding
themolecularbasisforthevarioussyndromesassociatedwithinsulinresistance.
Secondly, we are now seeing a global epidemic of Type 2 diabetes that may
pose a major threat to international public health. Thirdly, the pharmaceutical
and biotechnology industries are investing heavily in the development of new
drugs thatcan improveinsulinaction. Therefore, webelievethatthepublication
of this book is timely.
Thereisconsiderableliteratureavailableonthesubjectofinsulinresistance.A
recentsearchonMedlinerevealedmorethan20,000articlesonthissubject.This
information is readily accessible and one might argue that a book such as this
onemightbecome outdatedassoon asitispublished! Oneguidingprinciplefor
this book was, therefore, tobring to the reader not only a synthesis of important
information, but also the wisdom of leading researchers and clinicians who are
recognised as leaders in their own fields.
Each chapter stands independently and is written by one or more experts on
the 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 insulin
actionandseparate chapters coverinsulinactioninrelationtoglucose,lipidand
protein metabolism. Section 2 explores the pathophysiological mechanisms of
insulin resistance, with discussion of the effects of glucose disposal in humans
andinanimalmodels.Italsoreviewsthecentralregulationofenergymetabolism
and its perturbation, as well as the relationship between fat distribution and
insulin action and the role of the nuclear hormone receptor PPARγ in glucose
metabolism. Finally, there is a chapter discussing the role of adipose tissue-
secreted products in causing insulin resistance. Section 3 examines the role of