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 diab etes. The purpose of this study was to determine whether there is a defect in basal, insulin-, and exercise-stimulated glucose transport in the skelet al muscle of these animals. IRS2(-/-) and wild-type (WT) mice (male, 8-10 w eeks) exercised on a treadmill for 1 h or remained sedentary. 2-Deoxyglucos e (2DG) uptake was measured in isolated soleus muscles incubated in vitro i n the presence or absence of insulin. Resting blood glucose concentration i n IRS2(-/-) mice (10.3 mM) was higher than WT animals (4.1 mM), but there w as a wide range among the IRS2(-/-) mice (3-25 mM), Therefore, IRS2(-/-) mi ce were divided into two subgroups based on blood glucose concentrations (I RS2(-/-)L < 7.2 mM, IRS2(-/-)H > 7.2 mM), Only IRS2(-/-)H had lower basal, exercise-, and submaximally insulin-stimulated 2DG uptake, while maximal in sulin-stimulated 2DG uptake was similar among the three groups. The ED50 fo r insulin to stimulate 2DG uptake above basal in IRS2(-/-)H was higher than WT and IRS2(-/-)L mice, suggesting insulin resistance in the skeletal musc le from the IRS2(-/-) mice with high blood glucose concentrations. Furtherm ore, resting blood glucose concentrations from all groups were negatively c orrelated to submaximally insulin-stimulated 2DG uptake (r(2) = 0.33, p < 0 .01). Muscle GLUT4 content was significantly lower in IRS2(-/-)H mice compa red with WT and IRS2(-/-)L mice. These results demonstrate that the IRS2 pr otein in muscle is not necessary for insulin- or exercise-stimulated glucos e transport, suggesting that the onset of diabetes in the IRS2(-/-) mice is not due to a defect in skeletal muscle glucose transport; hyperglycemia ma y cause insulin resistance in the muscle of IRS2(-/-) mice.