Insulin receptors in diabetes and other conditions

Abstract

The central role of insulin lack in the pathogenesis of diabetes has been recognized since the classic studies of Minkowski in pancreatectomized dogs and the subsequent isolation of insulin by Banting and Best. However, later studies demonstrating the diabetogenic effects of growth hormone and glucocorticoids raised the possibility that in some patients diabetes may be the consequence of resistance to, rather than the absence of, insulin. Although endocrine-associated diabetes is relatively rare, evidence that insulin insensitivity is a frequent phenomenon emerged following the introduction by Berson and Yalow of radioimmunoassay for the measurement of circulating insulin. Obese patients were observed to be hyperinsulinemic yet to have a markedly increased tendency towards the development of maturity-onset diabetes. The more recent discovery that the first step in the action of insulin, as in the case of other polypeptide hormones, is its binding to a spccific cell surface receptor [I]. has led to new insights regarding the cellular mechanisms regulating tissue sensitivity to insulin in health as well as disease. Insulin receptors on target cells serve two major functions: (11 specific recognition of insulin molecules amongst other circulating hormones and substrates, and [2) the triggering of a chain of intracellular events resulting in increased transport of substrates (e.g., increased glucose uptake by fat cells] or altered enzyme activity (e.g., stimulation of glycogen synthase and inhibition of phosphorylase). Although the precise chemical structure of the insulin receptor has not been defined, it is believed to be a glycoprotein with a molecular weight of 150,000 to 300,000 daltons [2]. The number of insulin receptors per cell is estimated to vary between 50,000 (in adipocytes] and 250,000 (in hepatocytes). However, maximal biologic effects are observed when only a small proportion (less than 10 per cent] of insulin receptors are occupied. The functional significance of the existence of “spare receptors” is that in circumstances in which a reduction in the number of receptors is the rate-limiting step in insulin action, a sufficient increase in the insulin concentration should lead to an increase in the number of receptor-hormone complexes so as to achieve the critical concentration