Introduction
T2D, adipose, skeletal muscle
ADVERSE EFFECTS, METABOLIC DISEASE
Glucocorticoids (GC) are prescribed to 2–3% of the population, most commonly for their anti-inflammatory actionsAt a cellular level, the ability of GCs to bind to, and activate the GC receptor, is controlled by a series of enzymes including the 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 2) that interconvert active and inactive GCsIn preclinical studies, we have shown that 11β-HSD1 is critical in regulating the development of the adverse features associated with circulating GC excess. 11β-HSD1 knockout (KO) mice treated with high doses of GC fail to develop a classical Cushing’s phenotypeHighly potent and selective 11β-HSD1 inhibitors have been developed, initially as a potential therapy for patients with T2D and metabolic disease, although their beneficial effects on glucose levels were modestBased on the published literature that demonstrating the role of 11β-HSD1 to regenerate active GC as well as its tissue distribution (high levels of expression in metabolic tissues e.g. liver, adipose, skeletal muscle, and low levels of expression in immune-inflammatory cells), we hypothesised that selective and specific inhibition of 11β-HSD1 may represent an alternative strategy to limit the adverse effects of prescribed GCs without compromising their anti-inflammatory actions.Adopting an experimental medicine, proof-of-concept approach, we have performed, a randomised, double-blind placebo-controlled study to test whether AZD4017 limits the adverse metabolic and bone effects of prednisolone (20 mg daily for 7 days) in healthy male volunteers.