Insulin resistance, defined as a reduced biological action of
insulin, has emerged as a major factor in the development and
progression of a number of common non-communicable diseases in man.
The role of insulin resistance in the aetiology of type 2 diabetes
is particularly well-established. However, insulin resistance has
also come to be regarded as a key component of a broader syndrome
of common metabolic defects that conspire to increase the risk of
atherosclerotic coronary heart disease. The ramifications of
insulin resistance now embrace many different medical specialties.

The objective of this book is to summarize the current state of
knowledge about insulin resistance. Section 1 (Pathophysiology of
Insulin Resistance) considers the development of current concepts
of insulin resistance. This is followed by a critical review of
techniques for the assessment of insulin action in humans. The
section concludes with an outline of current hypotheses concerning
the molecular defects responsible for insulin resistance. Section 2
(Insulin Resistance in Clinical Medicine) broadens the discussion
to include physiological and pathological conditions with which
insulin resistance is associated; the effects of drug treatment on
insulin sensitivity are also considered. Section 3 (Management of
Insulin Resistance and Associated Conditions) focuses on the
avoidance and treatment of insulin resistance in its clinical
manifestations. A discussion of the potential benefits of
non-pharmacological measures prefaces a review of the range of
drugs used in the treatment of type 2 diabetes and related
disorders. References are confined to key articles at the end of
each section.

Improved nutrition allied to increased levels of physical exercise
are of crucial importance in the battle to stem the increasing
incidence and prevalence of insulin resistance; however,
translation of such advice into action has proved difficult in
practice. Thus, other approaches have been explored. Recent years
have witnessed considerable progress in the pharmacological
management of insulin resistance. In particular, the
thiazolidinediones (and other insulin-sensitizing drugs) appear to
provide a more specific assault on insulin-resistance. Clinical
experience with these agents remains relatively limited and serious
hepatotoxicity has clouded the first agent in this class -
troglitazone. With its introduction into the USA in 1995 and driven
by the publication of the United Kingdom Prospective Diabetes
Study, metformin has enjoyed a renaissance. This well-established
agent is finding application for new clinical indications. In
parallel, the development of anti-obesity drugs continues
apace.

The molecular and genetic mechanisms underlying some forms of
insulin resistance are being revealed.

Original intellectual concepts such as the fetal origins hypothesis
are challenging traditional views about the aetiology of insulin
resistance and its clinical sequelae. These exciting scientific
advances notwithstanding, the evolving global epidemic of obesity
and type 2 diabetes represents an enormous public health challenge.
Now more than ever, research must focus on identifying solutions
that are applicable on the level of entire populations. By
definition, these must also be practical and cost-effective.

This new book summarises the current state of knowledge on insulin resistance. Divided into three sections, the book first considers the development of current concepts of insulin resistance. This is followed by a critical review of techniques for the assessment of insulin action in humans. The section concludes with an outline of current hypotheses concerning the molecular defects responsible for insulin resistance. Section 2, Insulin Resistance in Clinical Medicine, broadens the discussion to include physiological and pathological conditions with which insulin resistance is associated; the effects of drug treatment on insulin sensitivity are also considered. The final section, Management of Insulin Resistance and Associated Conditions, focuses on the avoidance and treatment of insulin resistance in its clinical manifestations. A discussion of the potential benefits of non-pharmacological measures prefaces a review of the range of drugs used in the treatment of type 2 diabetes and related disorders. References are confined to key articles at the end of each section.

Section 1. Pathophysiology of insulin resistance.

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1.1 Introduction.

1.2 Normal physiology.

1.2.1 Hormonal regulation of metabolism.

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1.2.2 The insulin receptor.

1.2.3 Post-binding events.

1.2.4 Glucose metabolism.

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1.2.5 Lipid metabolism.

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1.2.6. Protein metabolism.

1.2.7. Ion transport.

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1.3 The concept of insulin resistance.

1.3.1 Early studies of insulin action.

1.4 Definitions of insulin resistance.

1.5 Assessment of insulin action in vivo.

1.5.1 Fasting insulin concentration.

1.5.2 Dynamic tests - endogenous insulin.

1.5.3 Dynamic tests - exogenous insulin.

1.5.4 Mathematical modelling techniques.

1.5.5 The insulin suppression test.

1.5.6 The hyperinsulinaemic euglycaemic clamp technique.

1.6. Mechanisms of insulin resistance.

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1.6.1 Genetic causes of insulin resistance.

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1.6.2 Acquired causes of insulin resistance.

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1.6.3.Fetal origins hypothesis.

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Further Reading.

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Section 2. Insulin resistance in clinical medicine.

2.1 Clinical features.

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2.2 Factors influencing insulin sensitivity.

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2.2.1 Normal variation in insulin action.

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2.2.2 Sex.

2.2.3 Age.

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2.2.4 Physical activity.

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2.2.5 Tobacco.

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2.2.6 Alcohol.

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2.3. Physiological states of insulin resistance.

2.3.1 Puberty.

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2.3.2 Pregnancy.

2.3.4 The menopause.

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2.4 Severe insulin resistance syndromes.

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2.5 Insulin resistance and cardiovascular risk.

2.5.1 Syndrome X.

2.5.2 Obesity.

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2.5.3 Regional adiposity.

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2.5.4 Impaired glucose tolerance.

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2.5.5 Type 2 diabetes.

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2.5.6 Essential hypertension.

2.5.7 Dyslipidaemia.

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2.5.8 Endothelial dysfunction.

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2.5.9 Microalbuminuria.

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2.5.10. Hyperuricaemia.

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2.5.11 Impaired Fibrinolysis.

2.5.12 Polycystic ovary syndrome.

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2.5.13 Non-alcoholic steatohepatitis.

2.6 Other disorders associated with insulin resistance.

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2.6.1 Counter-regulatory hormone secretion.

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2.6.2 Endocrinopathies.

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2.6.3 Chronic renal failure.

2.6.4 Cirrhosis.

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2.6.5 Cardiac failure.

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2.7 Miscellaneous inherited disorders.

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