Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli.
To test the hypothesis that glucocorticoids inhibit muscle glucose transport apart from changes in early insulin-signaling events, we determined the effect of glucocorticoid treatment on the activation of glucose transport by both insulin and non-insulin-related stimuli (insulin-like growth factor [IGF] I and hypoxia) in rat skeletal muscle. Male Sprague-Dawley rats were treated with dexamethasone (Dex) (0.8 mg/kg for 2 days) and compared with pair-fed controls. 2-[3H]deoxyglucose (2-[3H]DG) uptake in isolated soleus muscles was measured under conditions in which uptake reflects glucose transport activity. In control muscles, 2-[3H]DG uptake was stimulated 10-fold by insulin (10 nmol/l) or 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-[3H]DG uptake by 41 +/- 11% (mean +/- SE, P < 0.05) and basal 2-[3H]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-[3H]DG uptake by 29 +/- 2% (P < 0.01), and decreased hypoxia-stimulated 2-[3H]DG uptake by 61% (P < 0.01). Dex treatment increased soleus GLUT4 protein content by 11%. Thus, Dex treatment reduces basal glucose transport and decreases the maximal response of skeletal muscle glucose transport to insulin, the related hormone IGF-I, and the non-insulin-related stimulus hypoxia. These 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 subcellular trafficking.
Weinstein
S P
SP
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029.
Paquin
T
T
Pritsker
A
A
Haber
R S
RS
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003847:Deoxyglucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D000860:Hypoxia / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009132:Muscles / Q000033:anatomy & histology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D003847:Deoxyglucose