Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKA(y), and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose ( to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKA(y) mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKA(y) mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKA(y) mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKA(y) mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKA(y) mice after a 4-h fast. The results support previous suggestions that selective 11beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.