Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle*

Insulin receptor substrate-2-deficient (IRS2−/−) mice develop type 2 diabetes. The purpose of this study was to determine whether there is a defect in basal, insulin-, and exercise-stimulated glucose transport in the skeletal muscle of these animals. IRS2−/− and wild-type (WT) mice (male, 8–10 weeks) exercised on a treadmill for 1 h or remained sedentary. 2-Deoxyglucose (2DG) uptake was measured in isolated soleus muscles incubated in vitro in the presence or absence of insulin. Resting blood glucose concentration in IRS2−/−mice (10.3 mm) was higher than WT animals (4.1 mm), but there was a wide range among the IRS2−/− mice (3–25 mm). Therefore, IRS2−/− mice were divided into two subgroups based on blood glucose concentrations (IRS2−/−L < 7.2 mm, IRS2−/−H > 7.2 mm). Only IRS2−/−H had lower basal, exercise-, and submaximally insulin-stimulated 2DG uptake, while maximal insulin-stimulated 2DG uptake was similar among the three groups. The ED50 for insulin to stimulate 2DG uptake above basal in IRS2−/−H was higher than WT and IRS2−/−L mice, suggesting insulin resistance in the skeletal muscle from the IRS2−/− mice with high blood glucose concentrations. Furthermore, resting blood glucose concentrations from all groups were negatively correlated to submaximally insulin-stimulated 2DG uptake (r 2 = 0.33, p < 0.01). Muscle GLUT4 content was significantly lower in IRS2−/−H mice compared with WT and IRS2−/−L mice. These results demonstrate that the IRS2 protein in muscle is not necessary for insulin- or exercise-stimulated glucose transport, suggesting that the onset of diabetes in the IRS2−/− mice is not due to a defect in skeletal muscle glucose transport; hyperglycemia may cause insulin resistance in the muscle of IRS2−/− mice.

[1]  M. Czech,et al.  Signaling Mechanisms That Regulate Glucose Transport* , 1999, The Journal of Biological Chemistry.

[2]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[3]  Tatsuya Hayashi,et al.  Evidence for 5′AMP-Activated Protein Kinase Mediation of the Effect of Muscle Contraction on Glucose Transport , 1998, Diabetes.

[4]  K. Siddle,et al.  Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. , 1998, The Biochemical journal.

[5]  I. Tabata,et al.  Effects of high-intensity intermittent swimming on glucose transport in rat epitrochlearis muscle. , 1998, Journal of applied physiology.

[6]  G. Shulman,et al.  Disruption of IRS-2 causes type 2 diabetes in mice , 1998, Nature.

[7]  G. Lienhard,et al.  A Novel 160-kDa Phosphotyrosine Protein in Insulin-treated Embryonic Kidney Cells Is a New Member of the Insulin Receptor Substrate Family* , 1997, The Journal of Biological Chemistry.

[8]  J. Eckel,et al.  Molecular mechanisms of contraction-induced translocation of GLUT4 in isolated cardiomyocytes. , 1997, The American journal of cardiology.

[9]  G. Lienhard,et al.  The 60-kDa Phosphotyrosine Protein in Insulin-treated Adipocytes Is a New Member of the Insulin Receptor Substrate Family* , 1997, The Journal of Biological Chemistry.

[10]  J. Zierath,et al.  Insulin Receptor Substrate-1 Phosphorylation and Phosphatidylinositol 3-Kinase Activity in Skeletal Muscle From NIDDM Subjects After In Vivo Insulin Stimulation , 1997, Diabetes.

[11]  William Arbuthnot Sir Lane,et al.  Role of IRS-2 in insulin and cytokine signalling , 1995, Nature.

[12]  O. Pedersen,et al.  Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  F. Giorgino,et al.  Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. , 1995, The Journal of clinical investigation.

[14]  C. Kahn,et al.  Insulin action and the insulin signaling network. , 1995, Endocrine reviews.

[15]  J. Holloszy,et al.  Wortmannin inhibits insulin‐stimulated but not contraction‐stimulated glucose transport activity in skeletal muscle , 1995, FEBS letters.

[16]  M. Birnbaum,et al.  The Effects of Wortmannin on Rat Skeletal Muscle , 1995, The Journal of Biological Chemistry.

[17]  C. Kahn,et al.  Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene , 1994, Nature.

[18]  T. Yagi,et al.  Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1 , 1994, Nature.

[19]  J. Blenis,et al.  Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation , 1994, Molecular and cellular biology.

[20]  M. Kasuga,et al.  Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. , 1994, The Biochemical journal.

[21]  C. Kahn,et al.  The insulin signaling system. , 1994, The Journal of biological chemistry.

[22]  E. Ravussin,et al.  Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. , 1993, The New England journal of medicine.

[23]  Dominique,et al.  Defect in skeletal muscle phosphatidylinositol-3-kinase in obese insulin-resistant mice. , 1993, The Journal of clinical investigation.

[24]  M J Saad,et al.  Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance. , 1992, The Journal of clinical investigation.

[25]  C. Kahn,et al.  Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein , 1991, Nature.

[26]  A. Klip,et al.  Exercise modulates the insulin‐induced translocation of glucose transporters in rat skeletal muscle , 1990, FEBS letters.

[27]  R. DeFronzo The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.