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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 11β-hydroxysteroid dehydrogenase type 1 (11β-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, 11β-HSD1 has been validated as a therapeutic target, and currently almost all major pharmaceutical companies are investing in programmes developing selective 11β-HSD1 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 11β-HSD1 as a therapeutic target and summarize the reported data that describe the metabolic impact of selective 11β-HSD1 inhibition. © 2009 Future Medicine Ltd.

Original publication

DOI

10.2217/CLP.09.31

Type

Journal article

Journal

Future Lipidology

Publication Date

07/09/2009

Volume

4

Pages

439 - 447