Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

Abstract

Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11β-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11β-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. Methods.BVT.2733 was given to spontaneously hyperglycaemic KKA y mice for 7 days using subcutaneous osmotic mini-pumps. Results. BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11β-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. Conclusion/interpretation. These results suggest that a selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1528[Diabetologia ( -1532

Essential roles of 11β-HSD1 in regulating brown adipocyte function

“…11b-HSD1 null mice exhibited decreased white adipose depot, resistance to hyperglycemia induced by fat feeding, and increased hepatic insulin sensitivity (Alberts et al 2002, 2003, Kershaw et al 2005, Stewart & Tomlinson 2009. By contrast, increased 11b-HSD1 activity in WAT resulted in the development of visceral adiposity, hyperglycemia, and insulin resistance in morbidly obese patients (Kannisto et al 2004, Baudrand et al 2010.…”

Characterisation of 11β-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat

“…GCs are essential for adipocyte differentiation (Hauner et al 1987), inhibit omental preadipocyte proliferation (Tomlinson et al 2002), but interestingly, promote proliferation in the SC depot (Bader et al 2002). 11β-HSD1 overexpression in adipose tissues in rodent models induces obesity and the metabolic syndrome (Masuzaki et al 2001, 2003) and selective 11β-HSD1 inhibitors have been suggested as a novel therapeutic strategy (Alberts et al 2002, 2003, Hermanowski-Vosatka et al 2005). The identification of 11β-HSD1 in human orbital adipose tissue is an important finding and raises the possibility that the local generation of GC within this depot may be functionally important.…”

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing’s syndrome

“…Previous studies using this class of drug have found them to have beneficial effects upon glucose tolerance, insulin sensitivity, and dyslipidemia when administered to rodent models of obesity, type 2 diabetes, and the metabolic syndrome, including db/db, ob/ob, KKA y , ApoE -/-, and Ldlr 3KO mice (33,34,35,36,37). Furthermore, clinical studies using compounds developed by both Incyte Corporation (Wilmington, DE, USA) and Merck have since been administered to patients with type 2 diabetes and those 'failing' metformin therapy.…”