Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-I gene

We investigated the relationship of codon 972 polymorphism of the insulin r eceptor substrate-1 (IRS-1) gene with insulin resistance in the Japanese po pulation. Among 130 patients with type-2 diabetes mellitus (DM), we identif ied 6 who were heterozygous for the Gly972Arg mutation. Among 744 healthy s ubjects, 6 were heterozygous and 1 was homozygous for the mutation. A hyper insulinemic euglycemic clamp study was performed in 3 of 6 diabetic patient s with the heterozygous Gly972Arg mutation and in 60 without it. Both group s showed almost the same levels of insulin sensitivity (glucose infusion ra te, GIR = 50.2 +/- 3.0 vs. 51.3 +/- 12.1 mu mol/kg/min). Similarly, there w as no difference in insulin sensitivity between healthy subjects with and w ithout the mutation using the homeostasis model assessment (HOMA index = 1. 14 +/- 0.50 vs. 1.02 +/- 0.63). The frequency of the Gly972Arg allele was n ot increased in diabetic patients compared with control subjects even in ag ed (>50 years old) or obese (BMI greater than or equal to 25) subjects. Amo ng healthy subjects, we identified a 25-year-old male with the homozygous G ly972Arg allele. He was slightly obese (BMI = 25.5) but showed relatively h igh insulin sensitivity, almost equal to that of healthy subjects without t he mutation (GIR = 67.2 vs. 71.8 +/- 22.0 mu mol/kg/min). Because the GIR i n healthy subjects was significantly higher compared with that in type-2 DM patients, we speculate that another genetic or environmental factor produc ing a more deleterious effect on insulin sensitivity may exist in diabetic patients. We conclude that this gene abnormality does not play a role in th e pathogenesis of insulin resistance and type-2 DM. Copyright (C) 2000 S. K arger AG. Basel.