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J. Biol. Chem., Vol. 275, Issue 45, 34841-34844, November 10, 2000

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ACCELERATED PUBLICATION
Type 1 11-Hydroxysteroid Dehydrogenase Mediates Glucocorticoid Activation and Insulin Release in Pancreatic Islets^*

Behrous Davani^§, Akhtar Khan, Malin Hult^¶, Eva Mårtensson^¶, Sam Okret^§, Suad Efendic, Hans Jörnvall^¶, and Udo C. T. Oppermann^¶

From the  Department of Molecular Medicine, Karolinska Hospital, S 171 76 Stockholm, Sweden, the ^§ Department of Medical Nutrition, University Hospital, NOVUM, S 141 86 Huddinge, Sweden, and the ^¶ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S 171 77 Stockholm, Sweden

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/-hydroxyl conversion between receptor-binding 11-OH steroids and the nonbinding 11-oxo compounds, carried out by 11-hydroxysteroid dehydrogenases (11-HSDs). In this study, we determined the role of glucocorticoid conversion by 11-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of -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 11-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11-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.

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