Skeletal muscle insulin resistance in normoglycemic subjects with a strongfamily history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation

Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal musc le of such individuals is unknown. The present study was undertaken to dete rmine whether abnormalities in insulin-signaling events are present in norm oglycemic, nonobese subjects with a strong family history of type 2 diabete s. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies wer e performed in eight normoglycemic relatives of type 2 diabetic patients (F H+) 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 stimulati on of insulin receptor tyrosine phosphorylation. In contrast, the FH+ group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 ty rosine 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 +/- 0.0 53 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 su bjects with sufficient biopsy material for further study, phosphorylation o f 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, des pite normal insulin receptor phosphorylation, post-receptor signaling was r educed and was correlated with glucose disposal in muscle of individuals wi th a strong genetic background for type 2 diabetes.