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

Impaired glucose tolerance and non-insulin-dependent diabetes (NIDDM) are the pathologic consequence 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.