Genetic variants of modulators of insulin action

Abstract

The insulin resistance syndrome (IRS) is a common clinical condition whose aetiology is poorly understood and which is known to recognize a genetic background. Impairment in insulin receptor (IR) tyrosine-kinase activity has been demonstrated in tissues from insulin-resistant subjects. Several inhibitors of the insulin receptor tyrosine-kinase activity have been recently described and associated with human insulin resistance. Genes encoding for two of these inhibitors, namely PC-1 and PTP1-B, have been deeply studied. The obtained results are here reported. PC-1, a class II transmembrane ectoenzyme, modulates insulin sensitivity by different mechanisms, unravelled by the discovery of two genetic variants. A polymorphism in exon 4, namely K121Q, has been described to be strongly associated with insulin resistance. As compared to the more common K variant, the Q variant has a greater inhibitory activity on insulin receptor function and action, by interacting more strongly with the insulin receptor and significantly reducing receptor autophosphorylation, PC-1 Q variant also identifies type 1 diabetic patients with a faster progression of diabetic nephropathy (DN), a condition that may share some common genetic determinants with insulin resistance. Furthermore, a haplotype in the 3′-untranslated region modulates PC-1 expression in skeletal muscle and confers, therefore, an increased risk for insulin resistance. The mechanism of PC-1 overexpression was explained by an observed significant increase in haplotype-specific mRNA half life. PTP1-B, a nonreceptor-type protein-tyrosine phosphatase (PTPase) that physically interacts with and dephosphorylates the activated insulin receptor, is a major regulator of insulin sensitivity and body fat, as shown from experimental evidences in animal models. A number of polymorphic variants, identified in different populations, have been associated to insulin resistance and its associated clinical conditions. A 1484insG variation in the 3′-UTR region was associated with several features of insulin resistance. Subjects carrying the 1484insG variant showed PTP1-B mRNA overexpression in skeletal muscle, supposedly due to an mRNA stabilization, as demonstrated by transfection experiments. A rare missense variation, namely P387L, was found significantly associated with the risk of type 2 diabetes (T2D). Also, a silent third base polymorphism, namely 981CT, was found to be associated with higher risk of either impaired glucose tolerance (IGT) or type 2 diabetes. Altogether, these data clearly indicate that subtle mutations affecting genes encoding for proteins able to inhibit insulin receptor tyrosine-kinase activity may play a role in modulating susceptibility for insulin resistance and/or type 2 diabetes mellitus.