11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, 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 KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.

Levels of 11beta-HSD1 in islets from ob/ob mice are positively regulated by DHC and could be lowered by a selective 11beta-HSD1 inhibitor and a glucocorticoid receptor antagonist. Increased levels of 11beta-HSD1 were associated with impaired GSIS.

HÖ GBERG, HELENA, LARS ENGBLOM, ÅSA EKDAHL, VERONICA LIDELL, ERIK WALUM, AND PE TERIS ALBERTS. Temperature dependence of O 2 consumption; opposite effects of leptin and etomoxir on respiratory quotient in mice. Obesity. 2006;14:673-682. Objectives: The aims were to compare the temperature dependence of the metabolic rate in young ob/ob mice with that in mature ob/ob and db/db mice and to examine the effect on the metabolic substrate preference of leptin and etomoxir in ob/ob, C57BL/6J (wild-type), and db/db mice. Research Methods and Procedures:In vivo oxygen consumption and carbon dioxide production were continuously measured by indirect calorimetry, and body temperature and total locomotor activity were measured by an implanted transponder. Leptin, etomoxir, or vehicle was administered intraperitoneally. Results: The temperature dependence of the metabolic rate of mature ob/ob and db/db mice were similar to that in wild-type mice. In young 6-week-old ob/ob mice, the metabolic rate was almost doubled at 15°C. Leptin (2 ϫ 3 mg/kg) decreased the respiratory quotient (RQ) and carbon dioxide production but did not alter oxygen consumption, body temperature, or locomotor activity in ob/ob and C57BL/6J mice and had no effect in the db/db mice. Etomoxir (2 ϫ 30 mg/kg) enhanced RQ and decreased oxygen consumption, carbon dioxide production, and body temperature in ob/ob, C57BL/6J, and db/db mice. Total locomotor activity was reduced in ob/ob and C57BL/6J mice. Discussion: In young ob/ob mice, the temperature sensitivity was enhanced compared with mature mice. Leptin and etomoxir had opposite effects on metabolic substrate preference. Leptin and lowered environmental temperature increased the relative fat oxidation as indicated by decreased RQ, possibly through activation of the sympathetic nervous system.

The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.