Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle.
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.
Weinstein
S P
SP
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029.
Holand
A
A
O'Boyle
E
E
Haber
R S
RS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000009:adverse effects; D005938:Glucocorticoids / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D006943:Hyperglycemia / Q000139:chemically induced; D006946:Hyperinsulinism / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007536:Isomerism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000032:analysis* / Q000378:metabolism; D009124:Muscle Proteins; D009132:Muscles / Q000737:chemistry* / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014316:Tritium
D001578:Benzopyrans; D001786:Blood Glucose; D005938:Glucocorticoids; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D014316:Tritium; D003907:Dexamethasone; D003847:Deoxyglucose; D000077205:Pioglitazone; C066021:englitazone