Swali A, Walker E A, Lavery G G, Tomlinson J W, Stewart P M
Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
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.
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.
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.
目的/假设：暴露于过量糖皮质激素与胰腺β细胞损伤及葡萄糖刺激的胰岛素分泌（GSIS）降低有关。无活性的糖皮质激素（可的松、11-脱氢皮质酮）可被11β-羟基类固醇脱氢酶1型（11β-HSD1）转化为活性皮质醇和皮质酮，该过程需要NADPH作为辅因子，而NADPH由6-磷酸己糖脱氢酶（H6PDH）产生。我们研究了11β-HSD1在胰岛内的定位和活性，并确定了其在调节胰岛素和胰高血糖素分泌中的功能作用。
通过实时PCR检测人胰腺和小鼠胰岛中11β-HSD1（也称为HSD11B1）、糖皮质激素受体和H6PDH（也称为H6PD）的mRNA表达。通过免疫组织化学和免疫荧光检测11β-HSD1蛋白水平。在野生型（WT）以及11β-Hsd1基因敲除和H6pdh基因敲除小鼠的完整组织和分离胰岛中评估11β-HSD1活性。在与地塞米松孵育的分离小鼠胰岛中，分别通过放射免疫分析（RIA）和酶联免疫吸附测定（ELISA）分析胰高血糖素分泌和胰岛素分泌。
11β-HSD1在小鼠和人类胰岛外周与胰高血糖素共定位，但不与胰岛素或生长抑素共定位。地塞米松、11-脱氢皮质酮和皮质酮在低葡萄糖刺激后诱导GSIS和胰高血糖素分泌呈剂量依赖性降低。用特异性抑制剂降低11β-HSD1活性或在H6pdh基因敲除小鼠中进行的实验可逆转11-脱氢皮质酮的作用，但用皮质酮处理后无此效果。
结论/解读：α细胞内通过11β-HSD1进行的糖皮质激素局部再生调节胰高血糖素分泌，此外可能以旁分泌方式限制β细胞的胰岛素分泌。
