Jh. Youn et al., TIME COURSES OF CHANGES IN HEPATIC AND SKELETAL-MUSCLE INSULIN ACTIONAND GLUT4 PROTEIN IN SKELETAL-MUSCLE AFTER STZ INJECTION, Diabetes, 43(4), 1994, pp. 564-571
Citations number
44
Categorie Soggetti
Endocrynology & Metabolism","Medicine, General & Internal
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.