THE ANTIHYPERGLYCEMIC AGENT ENGLITAZONE PREVENTS THE DEFECT IN GLUCOSE-TRANSPORT IN RATS FED A HIGH-FAT DIET

The effects of englitazone in male Wistar rats fed a high-fat diet (59 % of calories as fat) were compared with control rats fed a high-carbo hydrate diet (69% of calories as carbohydrate) (5-15 animals per group ). Insulin-stimulated (17 nmol/l) 2-deoxy-D-glucose (2-DG) uptake was inhibited 31% in adipocytes isolated from rats on the high-fat diet fo r 3 weeks, but englitazone (50 mg/kg for the last 7 days) normalized t he response, There was a selective decrease in GLUT4 (54 +/- 5% of hig h-carbohydrate) in epididymal fat from rats on the high-fat diet for 3 weeks, but englitazone treatment did not reverse the defect in GLUT4 (43 +/- 8% of high-carbohydrate) or increase GLUT1 (81 +/- 12% of high -carbohydrate). Englitazone normalized oral glucose (1 g/kg body wt) i ntolerance and excessive (210% of high-carbohydrate) Liver glycogen de position (from [C-14]glucose) caused by the high-fat diet. The high-fa t diet tended to decrease insulin receptor substrate-1 (IRS-1) and pho sphatidylinositol-3'-kinase (PI-3-kinase) expression in epididymal fat (26% decrease; P < 0.1), Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) wher e it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-D G uptake, In summary, englitazone prevented the insulin resistance ass ociated with a high-fat diet, but the mechanism of action does not inv olve changes in fat or muscle glucose transporter content and may not involve activation of the insulin signaling pathway via PI-3-kinase.