Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets.
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/beta-hydroxyl conversion between receptor-binding 11beta-OH steroids and the nonbinding 11-oxo compounds, carried out by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). In this study, we determined the role of glucocorticoid conversion by 11beta-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11beta-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11beta-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of beta-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 11beta-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11beta-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.
Davani
B
B
Department of Molecular Medicine, Karolinska Hospital, S 171 76 Stockholm, Sweden.
Khan
A
A
Hult
M
M
Mårtensson
E
E
Okret
S
S
Efendic
S
S
Jörnvall
H
H
Oppermann
U C
UC
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007527:Isoenzymes; D007700:Kinetics; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014158:Transcription, Genetic
D000897:Anti-Ulcer Agents; D005938:Glucocorticoids; D007328:Insulin; D007527:Isoenzymes; D008024:Ligands; D012333:RNA, Messenger; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D005947:Glucose; D002229:Carbenoxolone; D003345:Corticosterone