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, Thongchai Pratipanawatr, Kenneth Cusi, Rachele Berria, John M. Adams, Christopher P. Jenkinson, Katsumi Maezono, Ralph A. DeFronzo, Lawrence J. Mandarino

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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, post-receptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2572-2578
Number of pages7
JournalDiabetes
Volume50
Issue number7-12
StatePublished - Nov 1 2001

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Pratipanawatr, W., Pratipanawatr, T., Cusi, K., Berria, R., Adams, J. M., Jenkinson, C. P., Maezono, K., DeFronzo, R. A., & Mandarino, L. J. (2001). 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. Diabetes, 50(7-12), 2572-2578.