The G972R variant of the Insulin Receptor Substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance

Aims/hypothesis. Insulin resistance is recognised as the core factor in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, hyperte nsion and atherosclerosis. Several studies indicate the possible role of mu tations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesi s of insulin-resistance and suggest a possible interaction between the IRS- 1 gene and obesity, either by an effect on the development of obesity or by causing or aggravating the obesity-associated insulin resistance. Therefor e, the prevalence of the G972R mutation of the IRS-1 gene was compared in 1 57 non-diabetic obese subjects (BMI > 30 m/kg(2)) and in 157 lean subjects (BMI < 28 m/kg(2)). By investigating the relation between this IRS-1 mutati on, measures of obesity and metabolic parameters, we explored the possible influence of this mutation on body fat distribution and insulin resistance. Methods. The G972R mutation was detected by PCR amplification and BstN-1 re striction enzyme digestion. Data were analysed by univariate and multivaria te analysis. Results. The G972R allele was significantly more frequent in obese subjects than in lean subjects (p < 0.002); however, no difference was found betwee n centrally and peripherally obese subjects. Obese G972R carriers had signi ficantly higher BMI (p < 0.001), fasting insulin (p < 0.01), triglycerides (p < 0.03) and HOMA(IR) (p < 0.001) than obese noncarriers. No differences were observed between G972R carriers and non-carriers among control subject s. Multivariate analysis confirmed that the IRS-1 G972R mutation was signif icantly and independently associated with reduced insulin sensitivity.(p < 0.009) in the obese group. Conclusion/interpretation. The G972R mutation of the IRS-1 gene associates with obesity, but not with fat distribution, in this Italian cohort, and wi thin the obese subjects this IRS-1 variant strongly associates with metabol ic parameters suggesting greater insulin-resistance. These findings indicat e a possible interaction between the IRS-1 variant and obesity in worsening insulin sensitivity.