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

Abstract

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.

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

“…Incubation of islets from ob/ob mice in the presence of 11-dehydrocorticosterone led to a dosedependent inhibition of insulin release, which was reversed with the non-selective 11β-HSD1 inhibitor, carbenoxolone, or with the selective 11β-HSD1 inhibitor, BVT.2733 [4,6]. However, this inhibition of insulin release could not be repeated using islets from normal (C57BL/6) mice [6]. The reason for this discrepancy is not clear, but it may relate to basal levels of 11β-HSD1.…”

“…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 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.…”

Functional and Molecular Aspects of Glucocorticoids in the Endocrine Pancreas and Glucose Homeostasis

“…Whereas inclusion of 11 -HSD1 inhibitors restored, addition of the GR antagonist attenuated the DHC-mediated inhibition of GSIS. (Ortsäter et al, 2005) Dex 100 nM for 3 d in BRIN-BD 11 cells DEX-treated cells lacked responsiveness to glucose and membrane depolarisation, and both PKA and PKC secretory pathways were desensitised. (Liu et al, 2006) Dex 1 µM concomitant or for 3 h previous culture in rat islets Dex (included in the perifusion solution) has no effect on GSIS.…”

“…It has been shown that presence of DEX in islet or -cell culture medium induces reduction (Gremlich et al, 1997) or no change (Shao et al, 2004) in GLUT 2 protein content, decrease in -cell GK (Shao et al, 2004) and pyruvate dehydrogenase (PDH) (Arumugam et al, 2010) activities, and increased pyruvate dehydrogenase kinase (PDK)-2 mRNA content (Arumugam et al, 2010). Despite alterations of these proximal metabolic components, the failure of -cells' response to glucose does not appear to involve a defect in the recognition of glucose, because no changes in the rate of glucose oxidation (Lambillotte et al, 1997;Zawalich et al, 2006), oxygen consumption (Ortsäter et al, 2005), NAD(P)H production (Lambillotte et al, 1997), or [Ca 2+ ]i (Lambillotte et al, 1997) have been observed. There are controversies related to Ca 2+ influx in response to glucose or non-glucidic stimuli (Myrsén-Axcrona et al, 1997;Koizumi & Yada, 2008), but in spite of elevation or reduction in Ca 2+ influx, there is consensus that Ca 2+ oscillations are impaired, which may harm the distal events of secretion dependent of finely tuned Ca 2+ handling.…”