11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets.
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 11beta-hydroxysteroid de...
| 主要な著者: | , , , , |
|---|---|
| フォーマット: | Journal article |
| 言語: | English |
| 出版事項: |
2008
|
| _version_ | 1826291389243064320 |
|---|---|
| author | Swali, A Walker, E Lavery, G Tomlinson, J Stewart, P |
| author_facet | Swali, A Walker, E Lavery, G Tomlinson, J Stewart, P |
| author_sort | Swali, A |
| collection | OXFORD |
| description | 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 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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. |
| first_indexed | 2024-03-07T02:58:40Z |
| format | Journal article |
| id | oxford-uuid:b02f9663-9fe5-493d-b62f-61ba4c4dd7c4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:58:40Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:b02f9663-9fe5-493d-b62f-61ba4c4dd7c42022-03-27T03:54:38Z11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b02f9663-9fe5-493d-b62f-61ba4c4dd7c4EnglishSymplectic Elements at Oxford2008Swali, AWalker, ELavery, GTomlinson, JStewart, P 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 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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. |
| spellingShingle | Swali, A Walker, E Lavery, G Tomlinson, J Stewart, P 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title | 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title_full | 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title_fullStr | 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title_full_unstemmed | 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title_short | 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets. |
| title_sort | 11beta hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets |
| work_keys_str_mv | AT swalia 11betahydroxysteroiddehydrogenasetype1regulatesinsulinandglucagonsecretioninpancreaticislets AT walkere 11betahydroxysteroiddehydrogenasetype1regulatesinsulinandglucagonsecretioninpancreaticislets AT laveryg 11betahydroxysteroiddehydrogenasetype1regulatesinsulinandglucagonsecretioninpancreaticislets AT tomlinsonj 11betahydroxysteroiddehydrogenasetype1regulatesinsulinandglucagonsecretioninpancreaticislets AT stewartp 11betahydroxysteroiddehydrogenasetype1regulatesinsulinandglucagonsecretioninpancreaticislets |