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The GlyArg⁹⁷² Amino Acid Polymorphism in Insulin Receptor Substrate-1 Affects Glucose Metabolism in Skeletal Muscle Cells¹

Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome-Tor Vergata (M.L.H., M.F., O.P., P.B., R.L., G.S.), Rome, Italy; Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health (D.L.), Bethesda, Maryland 20892; and Department of Medicine, Columbia University (D.A.), New York, New York 10027-6902

Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Interna, Università di Roma-Tor Vergata, Via Orazio Raimondo, 00173 Rome, Italy. E-mail: sesti{at}uniroma2.it

Molecular scanning of insulin receptor substrate-1 (IRS-1) revealed several amino acid substitutions. The most common IRS-1 variant, a Gly to Arg⁹⁷² change, is more prevalent among type 2 diabetic patients. In this study we overexpressed wild-type and Arg⁹⁷²IRS-1 variant in L6 skeletal muscle cells and examined the functional consequences of this polymorphism on insulin metabolic signaling. L6 cells expressing Arg⁹⁷²-IRS-1 (L6-Arg⁹⁷²) showed a decrease in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity compared with L6 cells expressing wild-type IRS-1 (L6-WT) as a consequence of decreased binding of p85 subunit of PI 3-kinase to IRS-1. L6-Arg⁹⁷² exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of both GLUT1 and GLUT4 translocated to the plasma membrane. Both basal and insulin-stimulated Akt phosphorylations were decreased in L6-Arg⁹⁷² compared with L6-WT. Basal glycogen synthase kinase-3 (GSK-3) activity was increased in L6-Arg⁹⁷² compared with L6-WT, and insulin-induced inactivation of GSK-3 was also reduced in L6-Arg⁹⁷². This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in L6-Arg⁹⁷² compared with L6-WT. These results indicate that the Arg⁹⁷²-IRS-1 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI 3-kinase/Akt/GSK-3 signaling pathway. The present data indicate that the polymorphism at codon 972 of IRS-1 may contribute to the in vivo insulin resistance observed in carriers of this variant.

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