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Regulation of 11β‐hydroxysteroid dehydrogenase type 1 and glucose‐stimulated insulin secretion in pancreatic islets of Langerhans
Author(s) -
Ortsäter Henrik,
Alberts Peteris,
Warpman Ulrika,
Engblom Lars O. M.,
Abrahmsén Lars,
Bergsten Peter
Publication year - 2004
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.525
Subject(s) - medicine , endocrinology , pancreatic islets , corticosterone , islet , 11β hydroxysteroid dehydrogenase type 1 , glucocorticoid , glucocorticoid receptor , secretion , biology , receptor , receptor antagonist , insulin , antagonist , chemistry , enzyme , dehydrogenase , hormone , biochemistry
Background In rodents, the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) converts inactive 11‐dehydrocorticosterone (DHC) into active corticosterone. The mRNA and activity of 11β‐HSD1 have been shown to be present in batch‐incubated pancreatic islets from the ob/ob mouse. In other tissues, 11β‐HSD1 expression has been demonstrated to be regulated by glucocorticoids. In the present study, the influence of DHC on 11β‐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 11β‐HSD1 verified the presence of 11β‐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 11β‐HSD1 protein than islets from the C57BL/6J mouse. When islets from ob/ob mice were cultured with 50 nM DHC, the 11β‐HSD1 levels doubled compared with islets cultured in the absence of DHC. Selective inhibition of 11β‐HSD1 attenuated DHC‐induced increase in 11β‐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 11β‐HSD1 inhibitors restored, addition of the glucocorticoid receptor antagonist attenuated the DHC‐mediated inhibition of GSIS. Conclusions Levels of 11β‐HSD1 in islets from ob/ob mice are positively regulated by DHC and could be lowered by a selective 11β‐HSD1 inhibitor and a glucocorticoid receptor antagonist. Increased levels of 11β‐HSD1 were associated with impaired GSIS. Copyright © 2004 John Wiley & Sons, Ltd.