To the editor: Insulin receptor substrate (IRS)-2 plays an important role in insulin signalling and its disruption, in mice, results in diabetes [1]. This could be attributed largely to hepatic insulin resistance and lack of beta cell compensation [2]. Although IRS-2 knock-out mice have a similar body weight to wild-type mice, they have twice as much body fat [3]. Because the severity of diabetes increases rapidly with weight gain in these mice, it can be hypothesised that a lack of IRS-2 is especially important in the development of obesity. In humans, a number of polymorphisms have been identified in the IRS-2 gene, the most common of which is represented by the Gly1057Asp substitution. We have previously investigated whether this polymorphism is associated with pre-diabetic phenotypes in non-diabetic people in our population from southern Germany. We did not find associations between the polymorphism and insulin sensitivity or insulin secretory function [4]. In an Italian population, the Gly1057Asp substitution was associated with a lower risk of Type 2 diabetes in lean people, but with a higher risk in obese people [5]. We therefore tested whether this polymorphism interacts with adiposity to affect insulin sensitivity and insulin secretory function in our population.

In our analysis we included 202 subjects with normal glucose tolerance [WHO criteria [6],(OGTT group)] from our Tübingen Family Study database. Subjects were studied using an OGTT and a euglycaemic hyperinsulinaemic clamp. A subgroup of 69 people (clamp group) underwent a modified hyperglycaemic clamp [7], and a third group of 20 people (lipid group) underwent two hyperglycaemic clamps (8 mmol/l, 140 min) before and after 5 h of infusion of Intralipid and heparin. For this study we obtained the approval of the local ethics committee and the consent of the families involved. The C-peptide plasma concentrations at 30 min during the OGTT were used as an estimate of beta cell function in the OGTT group. The first and second phase of C-peptide secretion during the hyperglycaemic clamp was calculated as the sum of the C-peptide concentrations from 2.5 to 10 min, and from 80 to 120 min respectively in the clamp group and the lipid group. Insulin sensitivity according to the insulin sensitivity index was measured during the hyperglycaemic clamp by relating the glucose infusion rate to the plasma insulin concentration during the second hour [7]. For statistical comparisons, an additive model and a recessive model were used [homozygotes (Asp/Asp) for the rare allele vs heterozygotes (Gly/Asp)