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

Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus brave 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 own that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoid, thereby playing a major role i local modulation of agonist concentration and activation of corticostroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-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 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemc mouse models 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 rice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression aspartate anotransferase, alone aminotrasferase and alkaline phosphtes, daily food intake and body weight were not altered by tire treatment. Conclusion/interpretation. These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can coma crew approach for lowering blood glucose concentrations in Type II diabetes.