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Endocrine Abstracts (2015) 37 S14.3 | DOI: 10.1530/endoabs.37.S14.3

University of Birmingham, Birmingham, UK.


Glucocorticoids (GCs) have physiological actions in almost all tissues, classically mediated by the GC receptor. The potent effects of GCs upon metabolic phenotype are best exemplified in patients with circulating GC excess (Cushing’s syndrome), who develop central (visceral) obesity, insulin resistance, myopathy, hypertension and in some cases overt type 2 diabetes (T2DM) and non alcoholic fatty liver disease (NAFLD). GCs are one of the most frequently prescribed class of medication, with 2–3% of UK and US populations currently receiving GC therapy. The clinical efficacy of GC therapy is not in doubt, but their ‘cushingoid’ side effects create significant morbidity and mortality and current prevention strategies to reduce the adverse metabolic consequences are limited. Tissue-specific availability of GC to bind and activate the GR is controlled by a series of pre-receptor regulatory enzymes. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active GC cortisol from inactive cortisone (corticosterone and 11-dehydrocorticosterone respectively in rodents) in adipose tissue, liver and muscle. Indeed, changes in GC availability, notably in adipose tissue, contribute significantly to the development of an adverse metabolic phenotype. Genetic and pharmacological inhibition of 11β-HSD1 in rodent and clinical studies improves the metabolic profile in obesity and T2DM models. This presentation will address how 11β-HSD1 contributes to promoting the unwanted metabolic aspects of GC excess and the ‘cushingoid’ phenotype often seen in patients taking GC therapy, with particular emphasis on adipose tissue specific GC effects. We propose that 11β-HSD1 inhibition may offer protection from a deleterious metabolic profile in the context of the GC excess state.

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