RELATIONSHIP BETWEEN INSULIN SENSITIVITY AND INSULIN-RECEPTOR SUBSTRATE-1 MUTATIONS IN NONDIABETIC RELATIVES OF NIDDM FAMILIES

Insulin receptor substrate-1 (IRS-1) occupies a key position in the in sulin-signalling pathway. Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the dev elopment of insulin resistance and non-insulin-dependent diabetes mell itus (NIDDM) remain controversial. Insulin resistance has been describ ed in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examine d the relationships between the two mutations and insulin senstivity i n 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess i nsulin sensitivity (K-ITT) were performed. Basal insulin sensitivity w as assessed by homeostasis model assessment (HOMA). Comparisons were m ade between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without ei ther (n = 80). General linear model analysis was used to compare K-ITT and HOMA between the subgroups with the anthropometric variables know n to influence insulin sensitivity as covariates. There were no signif icant differences between the subgroups for K-ITT and HOMA. In conclus ion, the 513 and 972 mutations, alone and in combination, are not asso ciated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.