Overexpression of Bcl-xL in β-cells prevents cell death but impairs mitochondrial signal for insulin secretion
Overexpression of Bcl-xL in β-cells prevents cell death but impairs mitochondrial signal for insulin secretion
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DOI：
10.1152/ajpendo.2000.278.2.e340
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发表时间：
2000-02-01
影响因子：
5.1
通讯作者：
Polonsky, KS
中科院分区：
文献类型：
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作者：
Zhou, YP;Pena, JC;Polonsky, KS
为了研究Bcl-x(L)在胰腺β细胞中的作用，使用不同形式的大鼠胰岛素启动子产生了两个转基因系，与同卵对照相比，Bcl-x(L)在β细胞中的表达在fd1增加了2- 3倍，fd2增加了10倍以上。暴露于该信号素（10 μ M） 48 h后，Fd 1和Fd 2 Bcl-xL转基因小鼠的胰岛细胞活力损失明显低于野生型小鼠。出乎意料的是，在Fd 2和净Fd 1 Bcl-xL小鼠中观察到严重的葡萄糖耐受不良。两种转基因系的胰腺胰岛素含量和胰岛形态与对照无明显差异。然而，f2bcl -x(L)胰岛的胰岛素分泌和细胞内游离Ca2+ ([Ca2+](i))对葡萄糖和KCl的反应受损。此外，胰岛素和[Ca2+](i)对丙酮酸甲酯（PME）的反应在Fd 2 Bcl-x(L)胰岛中与葡萄糖类似地降低。与线粒体缺陷一致，fd2 Bcl-x(L)胰岛的葡萄糖氧化，而不是糖酵解，明显低于野生型胰岛。在f2bcl - xl胰岛中，葡萄糖、PME和α -酮异己酸诱导的线粒体膜电位、NAD(P)H和ATP产生的超极化也显著降低。因此，尽管Bcl-x(L)促进β细胞存活，但由于线粒体营养代谢和胰岛素分泌信号的缺陷，Bcl-xL的高水平表达会导致葡萄糖诱导的胰岛素分泌减少和高血糖。
To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines were produced using different forms of the rat insulin promoter Bcl-x(L) expression in beta-cells was increased 2- to 3-fold in founder (Fd 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 mu M for 48 h), losses of cell viability in islets of Fd I and Fd 2 Bcl-xL transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but net Fd 1 Bcl-xL mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca2+ ([Ca2+](i)) responses to glucose and KCl. Furthermore, insulin and [Ca2+](i) responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-xL islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-xL result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.