Skeletal Muscle Insulin Resistance in Normoglycemic Subjects With a Strong Family History of Type 2 Diabetes Is Associated With Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation

Skeletal Muscle Insulin Resistance in Normoglycemic Subjects With a Strong Family History of Type 2 Diabetes Is Associated With Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation Wilailak Pratipanawatr 1 , Thongchai Pratipanawatr 1 , Kenneth Cusi 1 , Rachele Berria 1 , John M. Adams 3 , Christopher P. Jenkinson 1 , Katsumi Maezono 1 , Ralph A. DeFronzo 1 and Lawrence J. Mandarino 1 2 3 1 Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2 Department of Biochemistry, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 3 Department of Physiology, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas Abstract 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, postrecept