Insulin Resistance: A Clinical Handbook

199 Pages·9.095 MB·English

by  Andrew J. Krentz(auth.)

INS U LIN RESISTANCE
A Clinical Handbook
To Alison, Jonathan and Robert
Insulin
Resistance
A Clinical Handbook
Andrew J. Krentz
MD,FRCP
Consultant in Diabetes and Endocrinology
Honorary Senior Lecturer in Medicine
Southampton University Hospitals, UK
Blackwell
Science
0 2002 by Blackwell Science Ltd
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First published 2002 by Blackwell Science Ltd
Library ofcongress Cataloging-in-PublicationD ata
Krentz,Andrew J.
Insulin resistance : a clinical handbook / Andrew J. Krentz.
p. cm.
Includes bibliographical references and index.
ISBN 0-632-05662-2
1. Insulin resistance-Handbooks, manuals, etc.
I. Title. [DNLM: 1. Insulin Resistance. WK820 K92i 20001
RC662.4 .K74 2000
616.4'6207-dc21
00-037824
ISBN 0-632-05662-2
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Contents
Preface, viii
About the author, ix
Acknowledgements, x
1 Pathophysiologyo f insulin resistance, 1
1.1 Introduction, 1
1.2 Normal physiology, 3
1.2.1 Hormonal regulation of metabolism, 3
1.2.2 The insulin receptor, 5
1.2.3 Post-binding events, 8
1.2.4 Glucose metabolism, 9
1.2.5 Lipid metabolism, 13
1.2.6 Protein metabolism, 14
1.2.7 Ion transport, 15
1.3 The concept ofinsulin resistance, 15
1.3.1 Earlystudies ofinsulin action, 15
1.3.2 Radioimmunoassays for insulin, 15
1.4 Definitions ofinsulin resistance, 17
1.5 Assessment of insulin action an vim, 19
1.5.1 Fasting insulin concentration, 19
1.5.2 Dynamic techniques-endogenous insulin, 24
1.5.3 Dynamic techniques-exogenous insulin, 25
1.5.4 Mathematical modelling techniques, 27
1.5.5 Insulin suppression test, 28
1.5.6 Hyperinsulinaemic euglycaemic clamp
technique, 29
1.5.7 Complementary techniques, 31
1.6 Mechanisms of insulin resistance, 34
1.6.1 Genetic defects, 34
1.6.2 Acquired forms of insulin resistance, 37
1.6.3 Fetal origins hypothesis, 44
1.7 Further reading, 47
2 Insulin resistance in clinical medicine, 50
2.1 Clinical features, 50
CONTENTS
2.2 Factors influencing insulin sensitivity, 52
2.2.1 Normal variation in insulin action, 52
2.2.2 Sex,56
2.2.3 Age,56
2.2.4 Physical exercise, 56
2.2.5 Tobacco, 58
2.2.6 Alcohol, 59
2.3 Physiological states of insulin resistance, 59
2.3.1 Puberty, 59
2.3.2 Pregnancy, 60
2.3.3 Menstrual cycle, 62
2.3.4 The menopause, 62
2.4 Severe insulin-resistance syndromes, 63
2.5 Insulin resistance and cardiovascular risk, 67
2.5.1 Syndrome X, 71
2.5.2 Obesity, 73
2.5.3 Regional adiposity, 78
2.5.4 Impaired glucose tolerance, 81
2.5.5 Type 2 diabetes mellitus, 83
2.5.6 Essential hypertension, 90
2.5.7 Dyslipidaemia, 94
2.5.8 Endothelial dysfunction, 98
2.5.9 Microalbuminuria, 98
2.5.10 Hyperuricaemia, 100
2.5.11 Impaired fibrinolysis, 101
2.5.12 Polycystic ovary syndrome, 103
2.5.13 Non-alcoholic steatohepatitis, 106
2.6 Other disorders associated with insulin resistance, 107
2.6.1 Counter-regulatory hormone secretion, 107
2.6.2 Endocrinopathies, 109
2.6.3 Chronic renal failure, 110
2.6.4 Hepatic cirrhosis, 11 1
2.6.5 Cardiac failure, 111
2.7 Miscellaneous inherited disorders, 111
2.8 Drug-induced insulin resistance, 113
2.9 Further reading, 114
3 Management of insulin resistance and
associated conditions, 119
3.1 Non-pharmacological measures, 119
3.1.1 Medical nutrition therapy, 11 9
3.1.2 Physical activity, 124
vi
CONTENTS
3.1.3 Alcohol, 128
3.1.4 Tobacco, 130
3.2 Drugs for type 2 diabetes, 131
3.2.1 Biguanides, 132
3.2.2 Thiazolidinediones, 140
3.2.3 Sulphonylureas, 151
3.2.4 Meglitinide analogues, 153
3.2.5 a-Glucosidase inhibitors, 155
3.2.6 Insulin, 157
3.3 Antiobesity drugs, 160
3.3.1 Sibutramine, 160
3.3.2 Orlistat, 161
3.3.3 Leptin, 161
3.3.4 P,-adrenocepter agonists, 163
3.4 Lipid-modifying drugs, 163
3.4.1 Fibric acid derivatives, 163
3.4.2 Acipimox, 164
3.4.3 Statins, 165
3.4.4 Omega-3 fatty acids, 166
3.5 Antihypertensive drugs, 166
3.5.1 P-Adrenergic blockers and thiazide
diuretics, 167
3.5.2 Calcium-channelb lockers, 168
3.5.3 Angiotensin converting enzyme inhibitors, 169
3.5.4 Angiotensin I1 receptor antagonists, 170
3.5.5 a,-Receptor blockers, 170
3.5.6 Selective imidazoline receptor agonists, 170
3.5.7 Aspirin, 170
3.6 Experimental therapies, 171
3.6.1 D-chzro-inositol, 171
3.6.2 Non-thiazolidinedione PPAR-y agonists, 172
3.6.3 a-Lipoic acid, 172
3.6.4 Insulin-like growth factor-l,173
3.6.5 Vanadium salts, 173
3.6.6 The search for new drugs, 174
3.7 Further reading, 174
Index, 179
Preface
Previously a sub-speciality interest among diabetologists,
insulin resistance has become relevant to clinicians in many
specialties-cardiology and reproductive medicine being
two prominent examples. This book aims to provide an
introduction to insulin resistance for clinicians who do not
have an extensive knowledge of metabolic medicine.
From my perspective as a clinical investigator I have
sought to emphasize the clinical implications of current
knowledge. I have also pointed out continuing uncer-
tainties, of which there is no shortage! The complex inter-
actions between genes and environment, for example,
caution against optimism for an early resolution of some
hndamental issues.
I have tried to produce a balanced overview that sets the
scene for hture developments. Early in this new millen-
nium it seems reasonable to express cautious optimism
about hture therapeutic prospects. However, alarming
rates ofobesity, type 2 diabetes and the metabolic syndrome
emphasize the need for more effective interventions.
Comments are welcome at [email protected].
A.J . Krentz
Southampton, Spring 2002
...
Vlll
About the author
Dr Krentz qualified from the University of Birmingham,
UK and trained in diabetes and endocrinology in Birmingham
and Albuquerque, USA. His doctoral thesis focused on the
regulation of intermediary metabolism in insulin-resistant
states. Dr Krentz is an active member of the European
Group for the study of Insulin Resistance (EGIR) and con-
tributes to the editorial boards of several scientific journals.
ix
Acknowledgements
My thanks go to Andrew Robinson, Gina Almond and
Alison Brown of Blackwell Science for advice, encourage-
ment and practical support. Mentors who have my grati-
tude include Malcolm Nattrass, David Schade and Cliff
Bailey. Peter Hale, Dev Singh, Penny Clark, Janet Smith
and others made invaluable contributions to the metabolic
studies cited from the General Hospital, Birmingham, UK.
Malcolm Nattrass and Peter Hale developed the low-dose
incremental inhsion technique discussed in section 1S .3.
x