8 Genetics of insulin action

Abstract

Insulin action is highly likely to be primarily genetically determined (given a permissive or facilitative environment, for example sufficient calorie availability), as shown by variations in ethnic distribution, evidence for familial transmission and genotypic responses to experimentally induced metabolic stresses. Further, it is likely that the genetic predisposition to insulin resistance is closely linked to (or perhaps synonymous with) the predisposition to develop overt NIDDM. Alternatively, in the development of diabetes, the genetic basis for insulin resistance may be necessary, but not sufficient, requiring a second major gene for beta-cell vulnerability (e.g. exhaustion, deterioration of function, amyloid deposition). The future examination of the genetics of insulin action depends in large measure on the method of assessment of insulin action that is selected and its consistent application to individuals, families and populations. The phenomenological approaches currently being used to describe and define insulin resistance could be identifying many different disorders, all leading to an apparent decrease or impairment of insulin action compared with that in 'normals'. Selection of any method for determining the presence of insulin resistance, together with selection of the threshold for 'present versus absent' is, at best, difficult. It is further complicated by the frequent association of insulin resistance with a wide range of disturbances, including hypertension, dyslipidaemia and glucose intolerance--the insulin resistance 'syndrome'. A number of possible loci and candidate genes controlling insulin action have been studied, and most have been ruled out as the probable underlying cause of the majority of cases of defective insulin action. Among those genes that are unlikely to be determinants of insulin resistance (except in a few rare cases of mutations) are those for insulin, the insulin receptor, glucose transporters and the genes for many specific enzymes. While these are unlikely to be responsible for insulin resistance, such potential genetic defects cannot be fully excluded using present methods. Direct gene sequencing of polymerase-chain-reaction amplified DNA may be the ultimate approach to identifying the critical defects underlying insulin resistance. Other candidate genes regulating insulin action are likely soon to come forth, such as those controlling the generation and function of the intracellular mediators of insulin action.(ABSTRACT TRUNCATED AT 400 WORDS)