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J Biol Chem, Vol. 274, Issue 30, 20791-20795, July 23, 1999

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

Yasuki Higaki, Jørgen F. P. Wojtaszewski, Michael F. Hirshman, Dominic J. Withers, Heather Towery, Morris F. White, and Laurie J. Goodyear

From the  Research Division and  Howard Hughes Medical Institute, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215

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 (r² = 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.

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