Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes

The insulin receptor substrate-2 (IRS-2) is a major insulin signalling mole cule, IRS-2 inactivation in mice induces a form of diabetes characterized b y peripheral insulin resistance and reduced beta cell mass, We tested the h ypothesis that a common nonconservative amino acid substitution of IRS-2 (G 1057D) might interact with overweight in the pathogenesis of type 2 diabete s. The variant was genotyped in 193 Italian patients with type 2 diabetes a nd 206 control subjects, In the absence of overweight, the risk of type 2 d iabetes decreased according to the dosage of the D1057 allele (odds ratio f or GD genotype 0.46 [95% CI 0.25-0.86]; DD genotype 0.18 [0.04-0.68]; P for trend = 0.0012). Conversely, the interaction between overweight and genoty pe increased the risk of type 2 diabetes according to the dosage of the D10 57 allele (odds ratio for GD genotype 2.50 [1.11-5.65]; DD genotype 5.74 [1 .11-29.78]; P for trend = 0.0047), Among controls, tasting C-peptide levels , after adjustment for plasma glucose, were inversely related to the dosage of the D1057 allele (P = 0.020). This finding suggested that carriers of t he D1057 allele may have higher insulin sensitivity and supported the prote ctive effect of this allele, Conversely, among overweight patients there wa s a parallel increase in fasting plasma glucose (P for trend = 0.037) and f asting C-peptide according to the dosage of the D1057 allele, suggesting th at higher insulin resistance and relative beta cell failure contributed to the increased risk of type 2 diabetes in overweight carriers of this allele , These data provide evidence for a strong association between type 2 diabe tes and the G1057D common genetic variant of IRS-2, which appears to be pro tective against type 2 diabetes in a codominant fashion, Overweight appears to modify the effect of this polymorphism toward a higher risk of type 2 d iabetes, Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive wei ght.