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

Abstract

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which requires NADPH as cofactor, which is generated by hexose-6-phosphate dehydrogenase (H6PDH). We investigated the localisation and activity of 11β-HSD1 within pancreatic islets, and determined its functional role in the regulation of insulin and glucagon secretion. Methods mRNA expression of 11β-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. 11β-HSD1 protein levels were examined by immunohistochemistry and immunofluorescence. 11β-HSD1 activity was assessed in intact tissue and isolated islets of wild-type (WT) and both 11β-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 11β-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 11β-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 11β-HSD1 within alpha cells regulates glucagon secretion and in addition may act in a paracrine manner to limit insulin secretion from beta cells.

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…In contrast, incubation of mouse pancreatic islets with dexamethasone (0.5-50 nM), corticosterone (50 nM) or 11-dehydrocorticosterone (50 nM) for 2 h reduced glucagon secretion induced by low glucose levels, effects that were reversed by a GR antagonist (Swali et al 2008). The inhibitory action of 11-dehydrocorticosterone was partially reversed by a selective 11b-HSD1 inhibitor.…”

“…The inhibitory action of 11-dehydrocorticosterone was partially reversed by a selective 11b-HSD1 inhibitor. This fact, along with the co-localisation of this enzyme in human and rodent islet a-cells, indicates that this islet cell type serves an important local function in pancreatic GC metabolism (Swali et al 2008). This situation may be different in other species, for example in rats, where this enzyme is expressed in non-a-cells (Rafacho et al 2014).…”

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). Again more work is required to dissect the functional role of glucocorticoids and 11 -HSD1 in the endocrine pancreas.…”

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

“…A 11-β-HSD-1 a hasnyálmirigy alfa-sejtjeiben direkt módon szabályozza a glükagonszekré-ciót. Az alfa-sejtek glükokortikoidelválasztása parakrin hatás, amely hatással lehet a szomszédos béta-sejtek inzulinelválasztására is, így eredményezve csökkent inzulintermelést [11].…”