Endocrine Abstracts

The global epidemic of obesity and type 2 diabetes has hastened the need to identify novel and efficacious therapies. Based upon parallels with Cushing’s syndrome, tissue specific cortisol excess, independent of circulating levels, has been suggested to have a crucial pathological role and may represent a potential treatment target. In key metabolic target tissues (liver, adipose and muscle), the endoluminal enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses glucocorticoid activation of cortisone to cortisol. Rodent models and translation clinical studies have validated its potential as a therapeutic target and pharmacological and genetic manipulation in rodents have show significant metabolic benefits. Selective 11β-HSD1 inhibitors for use in clinical studies have now been developed and clinical data are emerging. Whilst these compounds appear to improve glycaemic control in patients with diabetes and cause improvements in blood pressure and decrease weight some concerns still remain. The magnitude of the clinical benefit that they confer remains to be fully determined and in most studies they cause activation of the hypothalamo–pituitary–adrenal axis. In addition, they have the potential to limit the endogenous anti-inflammatory actions of glucocorticoids, although clinical data to support this are lacking. Whilst their development has focussed on treating metabolic disease, alternative indications are emerging and further clinical studies are now warranted.