TIME COURSES OF CHANGES IN HEPATIC AND SKELETAL-MUSCLE INSULIN ACTIONAND GLUT4 PROTEIN IN SKELETAL-MUSCLE AFTER STZ INJECTION

To determine the relative time courses of changes peripheral and hepat ic insulin action and skeletal muscle GLUT4 protein levels after a str eptozotocin (STZ) injection in rats, we performed hyperinsulinemic (14 -18 nM), euglycemic (7.5 mM) clamps in control (n = 8) and diabetic ra ts at 1 (n = 7),3 (n = 8), 7 (n = 8), and 14 (n = 6) days after intrap eritoneal STZ (65 mg/kg). Basal plasma glucose concentrations increase d from 8.1 +/- 0.2 mM in control rats to 23.5 +/- 1.2 mM 1 day after S TZ (P < 0.01) and remained constant thereafter. Basal plasma insulin l evels were approximately 35% of control levels in all STZ groups (P < 0.01). Insulin-stimulated whole-body glucose uptake decreased signific antly as early as one day after STZ injection (P < 0.01), resulting pr edominantly from a decrease in whole-body glycolysis. Insulin action t o suppress hepatic glucose output was normal on day 1 after STZ but im paired markedly on day 3 and thereafter (P < 0.01). Insulin-stimulated glucose uptake in individual skeletal muscles was not altered until d ay 7 after STZ, and the magnitudes of decreases in skeletal muscle ins ulin action on days 7 and 14 were not fully accounted for by the decre ases in GLUT4 protein level measured from the same muscles. Our data i ndicate that there is a temporal hierarchy in the development of insul in resistance in STZ-induced diabetes. Insulin resistance is manifeste d initially (within one day) as a reduction in insulin-mediated glucos e uptake and glycolysis in tissues other than skeletal muscle; availab le data suggest that the liver is a potential site of the initial redu ction in insulin-mediated glucose uptake. Resistance of hepatic glucos e output to suppression by insulin appears next, by day 3. Insulin res istance in skeletal muscle appears last (between days 3 and 7 after ST Z administration), and the resistance in muscle cannot be fully accoun ted for by reduced GLUT4 expression.