Inhibition of 11β-hydroxysteroid dehydrogenase improves glucose metabolism in insulin resistant Otsuka long-evans Tokushima fatty rats

Abstract

Increased activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) has been implicated in the development of the metabolic syndromes by amplification of local glucocorticoid actions through regeneration of active glucocorticoid receptor. The present study was examined whether inhibition of 11β-HSD-1 by carbenoxolone (CBX), a non-selective 11β-HSD inhibitor, improved carbohydrate metabolism in insulin resistant Otsuka Long- Evans Tokushima Fatty (OLETF) rats or not. Rats received subcutaneous CBX, twice a day [50 mg/kg bodyweight (b.w.)] or vehicle for 2 weeks, and then were evaluated fasting blood glucose levels, glucose tolerance, serum fasting insulin levels, and blood lipid levels in the both groups. The fasting blood glucose and insulin were lower in CBXtreated OLETF rats at 2 weeks than those of compared to day 0 and vehicle-treated OLETF rats at 2 weeks. Blood glucose fluctuations of the CBX-treated OLETF rats were more normal than those of vehicletreated ones during intraperitoneal glucose tolerance tests. Blood concentrations of cholesterol and free fatty acids in the CBX-treated OLETF rats were lesser than those of vehicle-treated ones. The area under time-concentration curve (AUC120min) of blood glucose during the glucose tolerance test and of CBXtreated OLETF rats was significantly lower than that of the vehicle-treated ones, and insulinogenic index (ISI30min) was significantly different between CBXand vehicle-treated groups. These results suggested that inhibition of 11β-HSD-1 by CBX might be improved carbohydrate metabolism and lipid profile in the insulin-resistant OLETF rats. © 2011 The Pharmaceutical Society of Japan.