B. Davani et al., Type 1 11 beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets, J BIOL CHEM, 275(45), 2000, pp. 34841-34844
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.