11beta-hydroxysteroid dehydrogenase type 1 inhibitor: a novel therapeutic target in the metabolic syndrome

Abstract

The common metabolic syndrome phenotypically resembles the rare disorder Cushing’s syndrome. However, plasma cortisol level is within normal range. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally controls the availability of an active form of glucocorticoid (cortisol and corticosterone) for glucocorticoid receptor. Recent studies reported that obesity in humans and rodents correlates with enhanced activity of 11beta-HSD1 selectively in adipose tissue. 11beta-HSD1 - dependent glucocorticoid amplification in the fat tissue may explain the Cushing’s syndrome/metabolic syndrome paradox. The evidence of an altered intracellular glucocorticoid metabolism in the pathogenesis of the murine obesity with associated metabolic syndrome underpins the importance of selective 11beta-HSD1 inhibition as a novel target for drug development. Multiple pharmaceutical companies are searching intensively for the 11beta-HSD1 inhibitor with the intention to create drugs that treat disorders such as diabetes type 2, dyslipidemia, visceral obesity, atherosclerosis. Here we review the role of 11beta-HSD1 in the metabolic syndrome and discuss the impact of selective 11beta-HSD1 inhibition.