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Diabetologia

Published in:

01-11-2008 | Article

11β-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets

Authors: A. Swali, E. A. Walker, G. G Lavery, J. W. Tomlinson, P. M. Stewart

Published in: Diabetologia | Issue 11/2008

Abstract

Aims/hypothesis

Exposure to excess glucocorticoid is associated with pancreatic beta cell damage and decreased glucose-stimulated insulin secretion (GSIS). Inactive glucocorticoids (cortisone, 11-dehydrocorticosterone) are converted to active cortisol and corticosterone by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which requires NADPH as cofactor, which is generated by hexose-6-phosphate dehydrogenase (H6PDH). We investigated the localisation and activity of 11β-HSD1 within pancreatic islets, and determined its functional role in the regulation of insulin and glucagon secretion.

Methods

mRNA expression of 11β-HSD1 (also known as HSD11B1), glucocorticoid receptor and H6PDH (also known as H6PD) in human pancreas and murine islets was examined by real-time PCR. 11β-HSD1 protein levels were examined by immunohistochemistry and immunofluorescence. 11β-HSD1 activity was assessed in intact tissue and isolated islets of wild-type (WT) and both 11β-Hsd1- and H6pdh-null mice. Glucagon secretion and insulin secretion were analysed by RIA and ELISA respectively in isolated murine islets incubated with dexamethasone.

Results

11β-HSD1 co-localised with glucagon in the periphery of murine and human islets, but not with insulin or somatostatin. Dexamethasone, 11-dehydrocorticosterone and corticosterone induced a dose-dependent decrease in GSIS and glucagon secretion following low glucose stimulation. Reduction of 11β-HSD1 activity with specific inhibitors or in experiments carried out in H6pdh-null mice reversed the effects of 11-dehydrocorticosterone, but had no effect following treatment with corticosterone.

Conclusions/interpretation

Local regeneration of glucocorticoid via 11β-HSD1 within alpha cells regulates glucagon secretion and in addition may act in a paracrine manner to limit insulin secretion from beta cells.

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Title: 11β-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets
Authors: A. Swali
E. A. Walker
G. G Lavery
J. W. Tomlinson
P. M. Stewart
Publication date: 01-11-2008
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 11/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-1137-2

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