The antihyperglycemic agent englitazone prevents the defect in glucose transport in rats fed a high-fat diet

• Published in: Diabetes (New York, N.Y.) Vol. 45; no. 1; pp. 60 - 66
• Main Authors: STEVENSON, R. W, MCPHERSON, R. K, PERSSON, L. M, GENEREUX, P. E, SWICK, A. G, SPITZER, J, HERBST, J. J, ANDREWS, K. M, KREUTTER, D. K, GIBBS, E. M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 1996
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Animals; Benzopyrans - pharmacology; Biological and medical sciences; Biological Transport - drug effects; Blood Glucose - analysis; Deoxyglucose - metabolism; Dietary Carbohydrates - administration & dosage; Dietary Fats - administration & dosage; General and cellular metabolism. Vitamins; Glucose - metabolism; Glucose Transporter Type 1; Glucose Transporter Type 4; Glycogen - metabolism; Hypoglycemic agents; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Insulin resistance; Male; Medical sciences; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases; Phosphoproteins - metabolism; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Physiological aspects; Rats; Rats, Wistar; Thiazoles - pharmacology; Thiazolidinediones; Endocrinopathy; Pancreatic hormone; Rat; Biological transport; Rodentia; Lipids; Supplemented diet; Glucose; Insulin; Target tissue resistance; Signal transduction; Hypoglycemic agent; Vertebrata; Mammalia; Treatment; Animal; Carrier protein
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.45.1.60

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-carbohydrate 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 for 3 weeks, but englitazone (50 mg/kg for the last 7 days) normalized the response. There was a selective decrease in GLUT4 (54 +/- 5% of high-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) intolerance and excessive (210% of high-carbohydrate) liver glycogen deposition (from [14C]glucose) caused by the high-fat diet. The high-fat diet tended to decrease insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-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) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake. In summary, englitazone prevented the insulin resistance associated with a high-fat diet, but the mechanism of action does not involve changes in fat or muscle glucose transporter content and may not involve activation of the insulin signaling pathway via PI-3-kinase.