Regulation of 11beta-hydroxysteroid dehydrogenase type 1 and glucose-stimulated insulin secretion in pancreatic islets of Langerhans

Diabetes Metab Res Rev. Jul-Aug 2005;21(4):359-66. doi: 10.1002/dmrr.525.

Abstract

Background: In rodents, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone (DHC) into active corticosterone. The mRNA and activity of 11beta-HSD1 have been shown to be present in batch-incubated pancreatic islets from the ob/ob mouse. In other tissues, 11beta-HSD1 expression has been demonstrated to be regulated by glucocorticoids. In the present study, the influence of DHC on 11beta-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 11beta-HSD1 verified the presence of 11beta-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 11beta-HSD1 protein than islets from the C57BL/6J mouse. When islets from ob/ob mice were cultured with 50 nM DHC, the 11beta-HSD1 levels doubled compared with islets cultured in the absence of DHC. Selective inhibition of 11beta-HSD1 attenuated DHC-induced increase in 11beta-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 11beta-HSD1 inhibitors restored, addition of the glucocorticoid receptor antagonist attenuated the DHC-mediated inhibition of GSIS.

Conclusions: Levels of 11beta-HSD1 in islets from ob/ob mice are positively regulated by DHC and could be lowered by a selective 11beta-HSD1 inhibitor and a glucocorticoid receptor antagonist. Increased levels of 11beta-HSD1 were associated with impaired GSIS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Corticosterone / blood
  • Glucose / pharmacology*
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / metabolism
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Oxygen Consumption

Substances

  • Blood Glucose
  • Insulin
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Glucose
  • Corticosterone