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

Swali, A ; Walker, E A ; Lavery, G G ; Tomlinson, J W ; Stewart, P M

Diabetologia, 2008-11, Vol.51 (11), p.2003-2011 [Periódico revisado por pares]

Germany

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Título:
11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets
Autor: Swali, A ; Walker, E A ; Lavery, G G ; Tomlinson, J W ; Stewart, P M
Assuntos: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism ; Animals ; Carbohydrate Dehydrogenases - metabolism ; Dexamethasone - pharmacology ; Enzyme Inhibitors - pharmacology ; Female ; Glucagon - metabolism ; Homeostasis ; Insulin - metabolism ; Insulin Secretion ; Islets of Langerhans - drug effects ; Islets of Langerhans - enzymology ; Islets of Langerhans - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Polymerase Chain Reaction ; Receptors, Glucocorticoid - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics
É parte de: Diabetologia, 2008-11, Vol.51 (11), p.2003-2011
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which requires NADPH as cofactor, which is generated by hexose-6-phosphate dehydrogenase (H6PDH). We investigated the localisation and activity of 11beta-HSD1 within pancreatic islets, and determined its functional role in the regulation of insulin and glucagon secretion. mRNA expression of 11beta-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. 11beta-HSD1 protein levels were examined by immunohistochemistry and immunofluorescence. 11beta-HSD1 activity was assessed in intact tissue and isolated islets of wild-type (WT) and both 11beta-Hsd1- and H6pdh-null mice. Glucagon secretion and insulin secretion were analysed by RIA and ELISA respectively in isolated murine islets incubated with dexamethasone. 11beta-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 11beta-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. Local regeneration of glucocorticoid via 11beta-HSD1 within alpha cells regulates glucagon secretion and in addition may act in a paracrine manner to limit insulin secretion from beta cells.
Editor: Germany
Idioma: Inglês

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

Swali, A ; Walker, E A ; Lavery, G G ; Tomlinson, J W ; Stewart, P M

Germany

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