Effects of glucocorticoids on fat mass and the therapeutic potential of targeting II beta-hydroxysteroid dehydrogenase type I in obesity

The epidemic of obesity and Type 2 diabetes has driven the need for novel and efficacious treatments. Based upon parallels in patients with glucocorticoid excess or Cushing's syndrome, glucocorticoid action has emerged as a novel target for therapy. In the vast majority of obese patients and those with Type 2 diabetes, circulating cortisol levels are not elevated. However, within key metabolic target tissues, the enzyme II beta-hydroxysteroid dehydrogenase type 1 (II beta-HSD1) converts the inactive glucocorticoid, cortisone, to cortisol, which is then available to bind and activate the glucocorticoid receptor and thus amplify local glucocorticoid action. In a series of in vitro rodent and clinical studies, II beta-HSDI has been validated as a therapeutic target, and currently almost all major pharmaceutical companies are investing in programmes developing selective II beta-HSDI inhibitors. In rodent models of obesity and diabetes, these compounds increase insulin sensitivity, improve glucose tolerance and glycemic control, decrease fasting insulin and lipid levels and decrease atherogenesis. Whilst they appear to be safe and well tolerated, clinical efficacy data on metabolic outcomes in humans have been slow to emerge and translation to the clinical setting remains the most pressing issue within the field. In this review, we present the evidence validating II beta-HSDI as a therapeutic target and summarize the reported data that describe the metabolic impact of selective II beta-HSDI inhibition.