Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal muscle of such individuals is unknown. The present study was undertaken to determine whether abnormalities in insulin-signaling events are present in normoglycemic, nonobese subjects with a strong family history of type 2 diabetes. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies were performed in eight normoglycemic relatives of type 2 diabetic patients (FH(+)) and eight control subjects who had no family history of diabetes (FH(-)), with each group matched for age, sex, body composition, and ethnicity. The FH(+) group had decreased insulin-stimulated glucose disposal (6.64 +/- 0.52 vs. 8.45 +/- 0.54 mg. kg(-1) fat-free mass. min(-1); P < 0.05 vs. FH(-)). In skeletal muscle, the FH(+) and FH(-) groups had equivalent insulin stimulation of insulin receptor tyrosine phosphorylation. In contrast, the FH(+) group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 +/- 0.077 vs. 1.328 +/- 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 +/- 0.053 vs. 0.466 +/- 0.098 activity units; P < 0.05). PI 3-kinase activity was correlated with the glucose disposal rate (r = 0.567, P = 0.02). In five subjects with sufficient biopsy material for further study, phosphorylation of Akt was 0.266 +/- 0.061 vs. 0.404 +/- 0.078 density units (P < 0.10) and glycogen synthase activity was 0.31 +/- 0.06 vs. 0.50 +/- 0.12 ng. min(-1). mg(-1) (P < 0.10) for FH(+) and FH(-) subjects, respectively. Therefore, despite normal insulin receptor phosphorylation, postreceptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes.