Type 1 11 beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets

Metabolic transformation of glucocorticoid hormones constitutes a determina nt of their cell-specific effects. The most important reaction for this cla ss of steroids is the reversible C11 keto/beta -hydroxyl conversion between receptor-binding 11 beta -OH steroids and the nonbinding 11-oxo compounds, carried out by 11 beta -hydroxysteroid dehydrogenases (11 beta -HSDs). In this study, we determined the role of glucocorticoid conversion by 11 beta -HSD in pancreatic islets and its function in the regulation of insulin rel ease. Pancreatic islets isolated from ob/ob mice display type 1 11 beta -hy droxysteroid dehydrogenase activity, i.e. in intact cells the reductive rea ction prevails, leading from dehydrocorticosterone to corticosterone. Expre ssion of type 1 11 beta -HSD mRNA was detected by reverse transcriptase-pol ymerase chain reaction in islets isolated from ob/ob mice and also from hum an tissue. Incubation of beta -cells in the presence of 11-dehydrocorticost erone leads to a dose-dependent inhibition of insulin release, indicating c ellular activation of 11-dehydrocorticosterone to the receptor ligand, furt her confirmed by reporter gene assays. Inhibition of 11 beta -HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11 beta -HSD in islets supports the concept that reactivation of inert circul ating hormone precursors in a cell-specific manner plays a major role in gl ucocorticoid physiology in rodents and man.