Type 1 11β-Hydroxysteroid Dehydrogenase Mediates Glucocorticoid Activation and Insulin Release in Pancreatic Islets

• Published in: The Journal of biological chemistry Vol. 275; no. 45; pp. 34841 - 34844
• Main Authors: Davani, Behrous, Khan, Akhtar, Hult, Malin, Mårtensson, Eva, Okret, Sam, Efendic, Suad, Jörnvall, Hans, Oppermann, Udo C.T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10-11-2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000600200

Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects. The most important reaction for this class of steroids is the reversible C11 keto/β-hydroxyl conversion between receptor-binding 11β-OH steroids and the nonbinding 11-oxo compounds, carried out by 11β-hydroxysteroid dehydrogenases (11β-HSDs). In this study, we determined the role of glucocorticoid conversion by 11β-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11β-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11β-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of β-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11β-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11β-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cell-specific manner plays a major role in glucocorticoid physiology in rodents and man.