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Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: Current status and therapeutic possibilities

Chapter
Part of the Progress in Drug Research book series (PDR, volume 51)

Summary

Impaired glucose tolerance and non-insulin-dependent diabetes (NIDDM) are the pathologic consequences of two co-incident and interacting conditions, namely insulin resistance and relative insulin deficiency. Recognised by the World Health Authority as a global health problem there are at 1995 estimates at least 110 million diagnosed diabetics world wide with at least the same number undiagnosed. Diabetes is the 4th leading cause of death in developed countries and its management exerts a vast economic and social burden. Insulin resistance is established as the characteristic pathologic feature of patients with glucose intolerance and NIDDM describing a state in which insulin stimulated glucose uptake and utilisation in liver, skeletal muscle and adipose tissue is impaired and coupled to impaired suppression of hepatic glucose output. Although the biochemical mechanisms underpinning both defects are becoming better understood, the genetic and molecular causes remain elusive; and whether insulin resistance or relative insulin deficiency represents the primary defect in patients with NIDDM is the matter of some debate. In this article we review the biochemical and molecular nature of the defects in insulin sensitivity and glucose uptake, and discuss some of the potential causative mechanisms. The genetic and environmental basis of insulin resistance is reviewed and presented, and potential therapeutic targets including thiazolidinediones are discussed.

Keywords

Insulin restistance hyperinsulinaemia non-insulin-dependent diabetes pathological mechanisms obesity liptoxicity glucotoxicity glucocorticoids inheritance and candidate genes thiazolidinediones PPARγ agonists metformin dehydroepiandrosterone TNFα thermogenesis sibutramine orlistat leptin uncoupling proteins 

Glossary of abbreviations

NIDDM

non-insulin dependent diabetes

IGT

impaired glucose tolerance

HGP

hepatic glucose production

TNFα

tumor necrosis factor α

WHO

World Health Organization

WHR

waist-to-hip ratio

OGIT

oral glucose tolerance test

BMI

body mass index

MRI

magnetic resonance imaging

FFA

free fatty acids

LPL

lipoprotein lipase

ZDF

diabetic obese Zucker rat

IDDM

insulin dependent diabetes

GFAT

glutamine fructose 6-phosphate amido transferase

PEPCK

phosphoenolpyruvate carboxykinase

MODY

Maturity Onset Diabetes in the Young

HNF

hepatic nuclear factor

US

United States

PPARγ

peroxisome proliferator activated receptor-γ

PPARα

peroxisome proliferator activated receptor-α

FDA

food and drugs authority

NDA

new drug application

DHEA

dehydroepiandrosterone

ACTH

adrenocorticotrophic hormone

MC2

melanocortin receptor 2

PVN

paraventricular nucleus

phen

phentermine

fen

fenfluramine

5-HT

5 hydroxytryptamine

D

dopamine

NAASCO

North American Association for the Study of Obesity

BAT

brown adipose tissue

UCP

uncoupling protein

QTL

quantitative trait locus

GDP

guanosine diphosphate

GABA

γ-aminobutyric acid

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© Springer Basel AG 1998

Authors and Affiliations

  1. 1.SmithKline Beecham PharmaceuticalsNew Frontiers Science Park (N)Harlow, EssexUK

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