Thiazolidine-2,4-diones, a new class of oral
antihyperglycemic agents, have been shown to be effective in improving
insulin sensitivity in a number of animal models of
insulin resistance, and recent investigation has suggested that the mechanism of action of these agents may include upregulation of the GLUT4 (
insulin-regulatable)
glucose transporter. We studied the efficacy of two of these agents,
pioglitazone and
englitazone, in preventing
glucocorticoid-induced
insulin resistance in rats, and examined the potential role of changes in GLUT4 expression in their action in skeletal muscle. Rats were treated with 0.1 mg/d
dexamethasone for 6 to 7 days with or without either
pioglitazone (10 mg/kg/d) or
englitazone (50 mg/kg/d). Both
thiazolidinediones decreased the elevated fasting serum
glucose and
insulin levels in
dexamethasone-treated animals.
Dexamethasone treatment alone decreased
insulin-stimulated
2-deoxyglucose uptake into isolated soleus muscles to 35% of control values. The addition of
pioglitazone or
englitazone increased
insulin-stimulated
2-deoxyglucose uptake by 74% and 57%, respectively. Whereas
dexamethasone treatment alone increased
GLUT4 protein content in rat soleus muscle by 25%, additional treatment with
pioglitazone or
englitazone did not further significantly alter GLUT4 levels. We conclude that
thiazolidinediones enhance
insulin responsiveness in skeletal muscle during
glucocorticoid treatment, but their mode of action in this setting is not via upregulation of GLUT4 expression.