Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 S13.3

ECE2007 Symposia Glucocorticosteroids (4 abstracts)

The 11β-hydroxysteroid dehydrogenase story

Jeremy Tomlinson


University of Birmingham, Birmingham, United Kingdom.


The global epidemic of obesity has heightened the need to understand the mechanisms that contribute to its pathogenesis and also to design and trial novel treatments. Patients with glucocorticoid (GC) excess, ‘Cushing’s syndrome’ share many phenotypic similarities to patients with simple obesity. GC availability to bind and activate the glucocorticoid receptor (GR) is controlled by the type 1 isoform of 11β-hydroxysteroid dehydrogenase (11β-HSD1) that converts inactive cortisone to cortisol and therefore amplifies local GC action. We have previously shown that expression of 11β-HSD1 is crucially important in both adipocyte differentiation and proliferation; Furthermore, over-expression specifically within adipose tissue leads to obesity and insulin resistance in rodent models. In addition, we have recently been able to show that inhibition of 11β-HSD1 in human adipose tissue can limit GC induced lipolysis. Selective 11β-HSD1 inhibitors (selective in that they block the activity of 11β-HSD1 and not 11β-HSD2 which inactivates cortisone to cortisol in mineralocorticoid target tissues) are currently in development although not yet available for use in clinical studies. Rodent studies utilizing these compounds have shown dramatic improvements in insulin sensitivity as well as improvements in lipid profiles and atherogenesis. The most fundamental question is whether these observations in rodents will translate to the clinical setting. It is likely that within the very near future, data from the first human studies will be available. If these compounds prove to be as efficacious in humans, then they may well represent an entirely novel, additional therapeutic strategy in the treatment of obesity, insulin resistance and type 2 diabetes.

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