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

Diabetologia. 2008 Nov;51(11):2003-11. doi: 10.1007/s00125-008-1137-2. Epub 2008 Sep 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Messenger / genetics
  • Receptors, Glucocorticoid / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Enzyme Inhibitors
  • Insulin
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • glucocorticoid receptor alpha
  • Dexamethasone
  • Glucagon
  • Carbohydrate Dehydrogenases
  • galactose-6-phosphate dehydrogenase
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1