Endocrine Abstracts

Excessive glucocorticoid action is detrimental to metabolic health. The last 15 years has seen the emergence of enzymatic intra-cellular glucocorticoid reactivation, driven by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), as a key mechanism contributing to glucocorticoid action. In most contexts, high intracellular glucocorticoid regeneration results in adverse metabolic effects. Inhibition or gene knockout of 11β-HSD1 is metabolically protective. Transgenic overexpression of 11β-HSD1 in adipose tissue and liver produces local and systemic defects in insulin sensitivity and nutrient metabolism akin to those found in human ‘metabolic syndrome’. Elevated 11β-HSD1 was also found in pancreatic islets from rodent ‘diabesity’ models. 11β-HSD1 activity was hypothesized to suppress insulin secretion and promote diabetes. We tested this hypothesis by overexpressing 11β-HSD1 specifically in β-cells using the mouse-I insulin promoter. Unexpectedly, we found that modest 11β-HSD1 overexpression protected β-cells against chronic high fat-diet-mediated dysfunction. Protection was associated with induction of a ‘super-differentiated’ state and reduced cellular stress that augmented insulin secretion. More recently we have found that mice overexpressing 11β-HSD1 in β-cells are protected from damage caused by the β-cell toxin streptozotocin. This effect is associated with modulation of inflammation and inflammatory resolution processes linked to β-cell destruction and survival. The unexpected beneficial effects of β-cell 11β-HSD1 elevation in these distinct contexts has prompted us to re-evaluate some potential therapeutic applications of glucocorticoid precursors.