The Arg(972) insulin receptor substrate-1 (IRS-1) variant has been hypothesized to play a role in pancreatic beta-cell stimulus-coupled insulin secretion and survival. We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes.