Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
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DOI：
10.1172/jci200319774
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发表时间：
2003-12-01
影响因子：
15.9
通讯作者：
Lowell, BB
中科院分区：
文献类型：
--
作者：
Krauss, S;Zhang, CY;Lowell, BB
2型糖尿病的一个重要特征是不能分泌足够量的胰岛素来应对葡萄糖浓度的增加。葡萄糖反应性丧失的机制尚不清楚。解偶联蛋白2（UCP2）由于其线粒体质子泄漏活性和随后对ATP产生的负面影响而损害葡萄糖刺激的胰岛素分泌。感兴趣的是，最近已经表明，超氧化物，当添加到分离的线粒体，激活UCP2介导的质子泄漏。由于肥胖和慢性高血糖增加线粒体超氧化物产生，以及胰腺β细胞中的UCP2表达，超氧化物-UCP2途径可能对肥胖和高血糖诱导的β细胞功能障碍有重要作用。这项研究表明，内源性产生的线粒体超氧化物激活UCP2介导的质子泄漏，从而降低ATP水平和损害葡萄糖刺激的胰岛素分泌。此外，高血糖症和肥胖症诱导的葡萄糖反应性丧失可通过减少线粒体超氧化物产生或UCP2基因敲除来预防。重要的是，在不存在UCP2的情况下，超氧化物的还原没有有益作用，并且在不存在UCP2的情况下，超氧化物水平进一步增加，这表明超氧化物对β细胞葡萄糖传感的不利影响是由UCP2的激活引起的。因此，超氧化物介导的UCP2激活可能在β细胞功能障碍和2型糖尿病的发病机制中发挥重要作用。
Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic beta cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced beta cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on beta cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of beta cell dysfunction and type 2 diabetes.