Type 1 11β-Hydroxysteroid Dehydrogenase Mediates Glucocorticoid Activation and Insulin Release in Pancreatic Islets

Abstract

Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects.The most important reaction for this class of steroids is the reversible C11 keto/␤-hydroxyl conversion between receptor-binding 11␤-OH steroids and the nonbinding 11-oxo compounds, carried out by 11␤-hydroxysteroid dehydrogenases (11␤-HSDs). In this study, we determined the role of glucocorticoid conversion by 11␤-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11␤-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11␤-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of ␤-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11␤-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11␤-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cellspecific manner plays a major role in glucocorticoid physiology in rodents and man.

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…11 -HSD1 is expressed in pancreatic islets and its expression is higher in islets from obese rodents where inhibition with carbenoxolone or selective 11 -HSD1 inhibitors (Davani et al, 2000, Ortsater et al, 2005 alleviates the 11-M a n u s c r i p t 14 ketoglucocorticoid-mediated suppression of insulin secretion in these models. An intriguing new finding suggests that 11 -HSD1 is expressed most highly in the glucagon secreting alpha cells, where the authors suggested the effects on insulin secretion might occur through a paracrine modulation of insulin secretion by this hormone (Swali et al, 2008).…”

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

“…While enzyme activity and cellular localisation studies have not been performed, incubation with 11-dehydrocorticosterone decreased glucose-stimulated insulin secretion (GSIS) in a dose-dependent manner. This was reversed by incubation with 11β-HSD1 inhibitors carbenoxolone [4,6] and BVT.2733 [6], and partially reversed by GR antagonist RU38486 [6].…”

“…11β-HSD1 is present at high levels in liver, adipose tissue and muscle, but it has also been reported to be present in pancreatic islets [4]. The activity of 11β-HSD1 primarily generates active glucocorticoid and cortisol (corticosterone in rodents) from inactive cortisone (11-dehydrocorticosterone in rodents) via its oxo-reductase activity [16].…”

“…11β-Hsd1 mRNA, and 11β-HSD1 protein and dehydrogenase activity have been detected in islets isolated from ob/ob mice [4,6]. While enzyme activity and cellular localisation studies have not been performed, incubation with 11-dehydrocorticosterone decreased glucose-stimulated insulin secretion (GSIS) in a dose-dependent manner.…”

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

“…In rodents, fetal exposure to glucocorticoids induces IUGR at birth, and impaired glucose tolerance [13][14][15] and hypertension [16,17] at adult age. Numerous studies have investigated the deleterious effects of glucocorticoids on pancreatic beta cell function, showing altered glucosestimulated insulin release, both in vitro in islets treated with dexamethasone [18][19][20] and in vivo in mice overexpressing GR in the beta cells [21,22].…”