INSULIN-RESISTANCE - INTERACTIONS BETWEEN OBESITY AND A COMMON VARIANT OF INSULIN-RECEPTOR SUBSTRATE-1

We previously discovered two aminoacid polymorphisms in codons 513 and 972 of the protein insulin receptor substrate-1 (IRS-1), which is imp ortant in cellular insulin action. We have investigated whether these polymorphisms are associated with changes in insulin sensitivity in a random sample of young healthy adults. Insulin sensitivity and secreti on were measured during a combined intravenous glucose and tolbutamide tolerance test in 380 unrelated white subjects aged 18-32. IRS-1 poly morphisms were examined conformation polymorphism and enzyme digestion . No homozygous carrier of the codon-513 variant was identified, but o ne non-obese man had the codon-972 mutation on both alleles. He had lo w fasting-serum insulin and C-peptide concentrations and low insulin s ensitivity and glucose effectiveness. During a 24 h dexamethasone test , he developed transient diabetes. In their heterozygous forms the cod on-513 and codon-972 variants of IRS-1 were found in 3% and 9% of the subjects. Non-obese carriers of either polymorphism had similar insuli n sensitivity and pancreatic beta-cell function to non-obese wild-type subjects (no known variants of IRS-1). Analysis of variance showed, h owever, a significant interaction between obesity (body-mass index gre ater than or equal to 25 kg/m(2)) and the heterozygous form of the cod on-972 variant (p<0.003); obese polymorphism carriers had lower insuli n sensitivity than obese non-carriers (mean 6.0 [SD 3.3] vs 12.3 [9.5] x 10(-5) L min(-1) pmol(-1)). The obese carriers of the codon-972 var iant were also characterised by a clustering of metabolic cardiovascul ar risk factors, with raised fasting concentrations of plasma glucose, serum triglyceride, and plasma tissue-plasminogen-activator and its f ast-acting inhibitor. With adjustment for known modulators of insulin sensitivity, multivariate analyses showed that the combination of obes ity and the codon-972 variant was associated with a 50% reduction in i nsulin sensitivity (p=0.0008). Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of co mmon insulin-resistant disorders.