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 KKAy 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.