Abstract
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 ED(50) 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.
Highlights
Conditions of impaired glucose tolerance and type 2 diabetes are characterized by defects in glucose handling by skeletal muscle, liver, and adipose tissue and an increase in pancreatic insulin secretion to compensate for the impaired insulin action
Our results show that IRS2 is not necessary for increases in glucose transport in response to insulin or exercise and suggest that it is the onset of hyperglycemia that results in skeletal muscle insulin resistance in IRS2-deficient mice
Neither IRS3 [28] nor IRS4 [29] are expressed in adult skeletal muscle. Both IRS1 and IRS2 are tyrosine-phosphorylated in response to insulin, and binding of tyrosine-phosphorylated IRS1 to the p85 regulatory subunit of PI 3-kinase and subsequent activation of the enzyme are thought to be important for insulin-stimulated glucose transport [8, 9]
Summary
Conditions of impaired glucose tolerance and type 2 diabetes are characterized by defects in glucose handling by skeletal muscle, liver, and adipose tissue and an increase in pancreatic insulin secretion to compensate for the impaired insulin action. IRS2-deficient mice exhibit both peripheral insulin resistance and impaired pancreatic -cell function and develop severe diabetes [14]. It is not known if insulin resistance in skeletal muscle is the primary factor leading to the development of diabetes in the IRS2-deficient animals. The activation of PI 3-kinase is necessary for insulin-stimulated glucose transport in skeletal muscle, whereas exercise stimulates GLUT4 translocation through a PI 3-kinase-independent mechanism (18 –21). Our results show that IRS2 is not necessary for increases in glucose transport in response to insulin or exercise and suggest that it is the onset of hyperglycemia that results in skeletal muscle insulin resistance in IRS2-deficient mice
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