Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes

The Gly 972 Arg variant in the insulin receptor substrate-1 (IRS-1) gene ma y interact with the pathogenesis of common insulin-resistance disorders rai sing the hypothesis that the mutation may predispose to type 2 diabetes. We examined the codon 972 variant in 144 non-diabetic first degree relative s of patients with type 2 diabetes (FDR), who underwent extensive phenotypi ng: Glucose tolerance was determined by an oral glucose load, insulin sensi tivity by euglycaemic-hyperinsulinaemic glucose clamp (glucose metabolic cl earance rate, MCR) and body composition by bioelectrical impedance. 20 (14% ) of the FDR showed the Gly 972 Arg variant in heterozygous form, 2 (1.3%) probands were homozygous Carriers of the polymorphism did not differ in MCR independent of body weight and total body fat. The polymorphism does not s eem to determine clamp-derived insulin sensitivity. Despite identical fasti ng plasma glucose, carriers of the polymorphism showed a slightly lower fas ting serum insulin and lower insulin response to an oral glucose load but h igher glucose concentrations In an obese subgroup (BMI > 25) the polymorphi sm did not show a higher frequency and was not associated with lower insuli n sensitivity. In the investigated group of young, healthy relatives of typ e 2 diabetes patients, the frequency of the mutation corresponded to that o f a diabetic population. In summary our data show that the polymorphism is not suitable to predict insulin resistance.