Endocrine Abstracts

Glucocorticoids (GC), such as prednisolone, are widely prescribed for their anti-inflammatory and immunosuppressive properties. However, they have significant side-effects including insulin resistance and hepatic steatosis. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone (11DHC) to active corticosterone (CORT) and thus amplifies local GC action. We hypothesise that enhanced local GC regeneration of exogenously administered GCs by 11β-HSD1 may contribute to the adverse side-effect profile. To test this hypothesis, 6-week-old male 11β-HSD1−/− and wildtype (WT) mice were treated with CORT (100 μg/ml), 11DHC (100 μg/ml) or vehicle via the drinking water. After 5 weeks, animals underwent glucose tolerance testing and were sacrificed for assessment of metabolic parameters. As anticipated, 11DHC treated 11β-HSD1−/− mice were indistinguishable from vehicle treated mice. CORT and 11DHC treated WT mice displayed impaired glucose tolerance, hepatic steatosis and increased hepatic expression of the fatty acid transporter CD36. However, 11β-HSD1−/− CORT treated mice were protected from glucose intolerance, hepatic steatosis and had lower hepatic CD36 expression. In CORT treated WT adipose tissue, 11β-HSD1 and hormone sensitive lipase (HSL) expression were elevated, associated with increased circulating free fatty acid (FFA) levels. Conversely, CORT treated 11β-HSD1−/− mice were protected from elevated HSL expression and increased circulating FFAs. Finally, intramyocellular diacylglyceride (DAG) content was elevated in CORT and 11DHC treated WT mice, whereas CORT treated 11β-HSD1−/− mice were protected from increased DAG levels, a possible factor in improved glucose tolerance. Importantly, both WT and 11β-HSD1−/− CORT treated mice had a similar increased circulating CORT (500 nmol/ml) compared to vehicle controls (50 nmol/ml). These data demonstrate that 11β-HSD1−/− mice are protected from the adverse effects of exogenous GC excess, and suggest that local GC regeneration may contribute significantly to the adverse effect profile of therapeutic GC use. This raises the possibility of using selective 11β-HSD1 inhibitors as an adjunctive therapy to limit the side-effects of GC treatment.

Declaration of funding

Medical Research Council (senior clinical fellowship ref. G0802765, Jeremy Tomlinson), the Wellcome Trust (program grant ref. 082809, Paul Stewart) and the Biotechnology and Biomedical Sciences Research Council (ref. BB/G023468/1, Gareth Lavery; ref. BBB/S/M/2006/13045, Stuart Morgan).