The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.
The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.
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DOI：
10.1016/j.taap.2011.11.002
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发表时间：
2012-01-15
影响因子：
3.8
通讯作者：
Gray, Joshua P.
中科院分区：
文献类型：
--
作者：
Heart, Emma;Palo, Meridith;Womack, Trayce;Smith, Peter J. S.;Gray, Joshua P.
关键词：
胰腺β细胞响应于葡萄糖从基础（4-7 mM）升高至刺激（8-16 mM）水平而释放胰岛素。β细胞对葡萄糖的代谢导致产生低水平的活性氧中间体（ROI），例如过氧化氢（H2 O2），这是一种新认识到的将葡萄糖代谢与胰岛素分泌联系起来的偶联因子。然而，高和毒性水平的H2 O2抑制胰岛素分泌。甲萘醌通过氧化还原循环机制以剂量依赖性方式产生H2 O2，研究了其对INS-1 832/13（大鼠β细胞胰岛素瘤细胞系）和原代啮齿类动物胰岛β细胞代谢和胰岛素分泌的影响。甲萘醌依赖的氧化还原循环和由此产生的H2 O2生产刺激葡萄糖下超过了几倍，达到基础葡萄糖。甲萘醌（0.1-10 μM）对胰岛素分泌的不同影响证实了这一点，在基础葡萄糖下，甲萘醌对胰岛素分泌有促进作用，但在刺激性葡萄糖下，甲萘醌对胰岛素分泌有抑制作用。甲萘醌和H2 O2形成的氧化还原循环依赖于糖酵解衍生的NADH，因为糖酵解的抑制和非生糖胰岛素促分泌素的应用不支持氧化还原循环。此外，质膜电子传递的活性，部分依赖于糖酵解衍生的NADH的系统，也被甲萘醌抑制。甲萘醌依赖的氧化还原循环是敏感的NQO 1抑制剂双香豆素和黄素蛋白抑制剂diphenyleneiodonium，这表明NQO 1和其他氧化还原酶在这个过程中的作用。这些数据可以解释明显的二分法之间的刺激和抑制作用的过氧化氢和甲萘醌对胰岛素分泌。
Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7 mM) to stimulatory (8-16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H2O2), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H2O2 inhibit insulin secretion. Menadione, which produces H2O2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H2O2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H2O2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H2O2 and menadione on insulin secretion.
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DOI：
10.1152/ajpendo.00673.2010
发表时间：
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影响因子：
5.1
作者：
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