Regulation of 11beta-hydroxysteroid dehydrogenase type 1 and glucose-stimulated insulin secretion in pancreatic islets of Langerhans.
BACKGROUND
In rodents, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone (DHC) into active corticosterone. The mRNA and activity of 11beta-HSD1 have been shown to be present in batch-incubated pancreatic islets from the ob/ob mouse. In other tissues, 11beta-HSD1 expression has been demonstrated to be regulated by glucocorticoids. In the present study, the influence of DHC on 11beta-HSD1 levels and glucose-induced changes in insulin secretion were studied in pancreatic islets isolated from the ob/ob mouse.


METHODS
Western blotting with antiserum for 11beta-HSD1 verified the presence of 11beta-HSD1 in islets from obese ob/ob and normal C57BL/6J mice. Insulin secretion was determined by perifusing islets and assaying the perifusate with ELISA.


RESULTS
Islets from the ob/ob mouse contained almost twofold more 11beta-HSD1 protein than islets from the C57BL/6J mouse. When islets from ob/ob mice were cultured with 50 nM DHC, the 11beta-HSD1 levels doubled compared with islets cultured in the absence of DHC. Selective inhibition of 11beta-HSD1 attenuated DHC-induced increase in 11beta-HSD1 levels, as did an antagonist of the glucocorticoid receptor. In individually perifused ob/ob mouse islets, early and late phases of glucose-stimulated insulin secretion (GSIS) were dose-dependently inhibited by 5, 50 and 500 nM DHC. Whereas inclusion of 11beta-HSD1 inhibitors restored, addition of the glucocorticoid receptor antagonist attenuated the DHC-mediated inhibition of GSIS.


CONCLUSIONS
Levels of 11beta-HSD1 in islets from ob/ob mice are positively regulated by DHC and could be lowered by a selective 11beta-HSD1 inhibitor and a glucocorticoid receptor antagonist. Increased levels of 11beta-HSD1 were associated with impaired GSIS.
Ortsäter
Henrik
H
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Henrik.Ortsater@medcellbiol.uu.se
Alberts
Peteris
P
Warpman
Ulrika
U
Engblom
Lars O M
LO
Abrahmsén
Lars
L
Bergsten
Peter
P
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010101:Oxygen Consumption
D001786:Blood Glucose; D007328:Insulin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D003345:Corticosterone