GLUCOCORTICOID-INDUCED INSULIN-RESISTANCE - DEXAMETHASONE INHIBITS THE ACTIVATION OF GLUCOSE-TRANSPORT IN RAT SKELETAL-MUSCLE BY BOTH INSULIN-RELATED AND NON-INSULIN-RELATED STIMULI

To test the hypothesis that glucocorticoids inhibit muscle glucose tra nsport apart from changes in early insulin-signaling events, we determ ined the effect of glucocorticoid treatment on the activation of gluco se transport by both insulin and non-insulin-related stimuli (insulin- like growth factor [IGF] I and hypoxia) in rat skeletal muscle. Male S prague-Dawley rats were treated with dexamethasone (Dex) (0.8 mg/kg fo r 2 days) and compared with pair-fed controls. 2-[H-3]deoxyglucose (2- [H-3]DG) uptake in isolated soleus muscles was measured under conditio ns in which uptake reflects glucose transport activity. In control mus cles, 2-[H-3]DG uptake was stimulated 10-fold by insulin (10 nmol/l) o r IGF-I(50 nmol/l) and sixfold by hypoxia. Dex treatment decreased 2-[ 3H]DG uptake at all concentrations of insulin tested, reducing maximal insulin-stimulated 2-[H-3]DG uptake by 41 +/- 11% (mean +/- SE, P < 0 .05) and basal 2-[H-3]DG uptake by 38 +/- 6% (P < 0.01). Dex treatment also inhibited 2-[3H]DG uptake at all concentrations of IGF-I tested, reducing maximal IGF-I-stimulated 2-[H-3]DG uptake by 29 +/- 20% (P < 0.01), and decreased hypoxia-stimulated 2-[H-3]DG uptake by 61% (P < 0.01). Dex treatment increased soleus GLUT4 protein content by 11%. Th us, Dex treatment reduces basal glucose transport and decreases the ma ximal response of skeletal muscle glucose transport to insulin, the re lated hormone IGF-I, and the non-insulin-related stimulus hypoxia. The se findings support the hypothesis that, in addition to altering early insulin-signaling events, glucocorticoids may also act by inhibiting the glucose transport system, per se, perhaps by affecting GLUT4 subce llular trafficking.