The role of 11beta-hydroxysteroid dehydrogenase in metabolic disease and therapeutic potential of 11beta-HSD1 inhibitors

Glucocorticoids play an essential role in the regulation of multiple physiological processes, including energy metabolism, maintenance of blood pressure and stress responses, as well as cognitive functions. On a tissue-specific level, glucocorticoid action is controlled by 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme (11beta-HSD1) is a NADP(H)-dependent bidirectional enzyme in vitro and reduces cortisone to active cortisol in vivo. 11beta-HSD1 is expressed in many tissues including the liver, adipose and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity has been associated with the metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that the inhibition of 11beta-HSD1 mitigates the adverse effects of excessive glucocorticoid levels on metabolic parameters and provides promising opportunities for the development of therapeutic interventions. This review discusses recently disclosed 11beta-HSD1 inhibitors and their potential for the treatment of metabolic disorders.