Aims/hypothesis: Insulin resistance is recognised as the core factor in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, hypertension and atherosclerosis. Several studies indicate the possible role of mutations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesis 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. Therefore, the prevalence of the G972R mutation of the IRS-1 gene was compared in 157 non-diabetic obese subjects (BMI > 30 m/kg2) and in 157 lean subjects (BMI < 28 m/kg2). By investigating the relation between this IRS-1 mutation, 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 restriction enzyme digestion. Data were analysed by univariate and multivariate analysis.
Results: The G972R allele was significantly more frequent in obese subjects than in lean subjects (p < 0.002); however, no difference was found between centrally and peripherally obese subjects. Obese G972R carriers had significantly higher BMI (p < 0.001), fasting insulin (p < 0.001), triglycerides (p < 0.03) and HOMAIR (p < 0.001) than obese non-carriers. No differences were observed between G972R carriers and non-carriers among control subjects. Multivariate analysis confirmed that the IRS-1 G972R mutation was significantly 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 within the obese subjects this IRS-1 variant strongly associates with metabolic parameters suggesting greater insulin-resistance. These findings indicate a possible interaction between the IRS-1 variant and obesity in worsening insulin sensitivity.