Insulin resistance : from clinical diagnosis to molecular genetics. Implications in diabetes mellitus

Insulin resistance is observed in several diseases such as non insulin depe ndent diabetes mellitus (NIDDM) or polycystic ovarian syndrome (PCOS). To u nderstand genetic determinism of this abnormality we have developed a multi disciplinary approach including selection of phenotypes with insulin resist ance confirmed in vivo by minimal model of Bergman anc characterization of cellular defects in insulin action on circulating erythrocytes and monocyte s. Exploration of variability in candidate genes by direct sequencing in so me genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gen e associated with major defects in insulin binding or kinase activity. In o ther rare genetic syndromes or patients affected by NIDDM or PCOS defects a ppear to be located at post-receptor level, where IRS (insulin receptor sub strate) genes are the most attractive candidates. Prevalence of some alleli c variants suggested a potential role of IRS genes in insulin resistance, a lthough their involvement in the pathogenesis of NIDDM remains controversia l. Genotype-phenotype correlations in first degree relatives of an index ca se caring the Type A syndrome, suggested that association of allelic varian ts of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synerg istic effects, to phenotypic expression of defects in signal tranduction. T hese mechanisms through genetic epistasis, involving several genes in insul in action, fit better with the polygenic nature of current forms of NIDDM a nd represent a good model in the study of pathogenesis of insulin resistanc e.