Mutant insulin receptors in syndromes of insulin resistance

Several distinct clinical syndromes are associated with marked resistance to the actions of insulin. In addition, insulin resistance plays a major role in the pathogenesis of non-insulin-dependent diabetes (De Fronzo, 1988) and is a central feature of a constellation of atherogenic metabolic alterations sometimes referred to as ‘Syndrome X’ (Reaven, 1988). The cloning of the human insulin receptor cDNA (Ullrich et al., 1985; Ebina et al., 1985) and more recently, the characterization of the receptor’s genomic organization (Seino et al., 1989) have allowed examination of t.he contribution of inherited defects in the receptor to the various syndromes of insulin resistance (Taylor S.I. et al., 1990; Taylor R., 1991). A decade or more of investigation in these various syndromes had led to the conclusion that a primary inherited defect of insulin action might be present. The finding of insulin receptor mutations in patients with these disorders has not only clarified the molecular basis of several clinical syndromes but has also complemented the intensive effort of basic scientists interested in the complex signalling functions of this molecule. Unlike site-directed mutants generated in vitro to test the structure/function relationships of various insulin receptor domains, naturally occurring mutations have provided unique ‘experiments of nature’ which are known in advance to have consequences for invivo metabolism.