Time Courses of Changes in Hepatic and Skeletal Muscle Insulin Action and GLUT4 Protein in Skeletal Muscle After STZ Injection

To determine the relative time courses of changes in peripheral and hepatic insulin action and skeletal muscle GLUT4 protein levels after a streptozotocin (STZ) injection in rats, we performed hyperinsulinemic (14–18 nM), euglycemic (7.5 mM) clamps in control (n = 8) and diabetic rats at 1 (n = 7), 3 (n = 8), 7 (n = 8), and 14 (n = 6) days after intraperitoneal STZ (65 mg/kg). Basal plasma glucose concentrations increased from 8.1 ± 0.2 mM in control rats to 23.5 ± 1.2 mM 1 day after STZ (P < 0.01) and remained constant thereafter. Basal plasma insulin levels were ∼ 35% of control levels in all STZ groups (P < 0.01). Insulin-stimulated whole-body glucose uptake decreased significantly as early as one day after STZ injection (P < 0.01), resulting predominantly from a decrease in whole-body glycolysis. Insulin action to suppress hepatic glucose output was normal on day 1 after STZ but impaired markedly on day 3 and thereafter (P < 0.01). Insulin-stimulated glucose uptake in individual skeletal muscles was not altered until day 7 after STZ, and the magnitudes of decreases in skeletal muscle insulin action on days 7 and 14 were not fully accounted for by the decreases in GLUT4 protein level measured from the same muscles. Our data indicate that there is a temporal hierarchy in the development of insulin resistance in STZ-induced diabetes. Insulin resistance is manifested initially (within one day) as a reduction in insulin-mediated glucose uptake and glycolysis in tissues other than skeletal muscle; available data suggest that the liver is a potential site of the initial reduction in insulin-mediated glucose uptake. Resistance of hepatic glucose output to suppression by insulin appears next, by day 3. Insulin resistance in skeletal muscle appears last (between days 3 and 7 after STZ administration), and the resistance in muscle cannot be fully accounted for by reduced GLUT4 expression.