Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species.
Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species.
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DOI：
10.1016/j.freeradbiomed.2010.12.020
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发表时间：
2011-03-01
影响因子：
7.4
通讯作者：
Brand, Martin D.
中科院分区：
文献类型：
--
作者：
Affourtit, Charles;Jastroch, Martin;Brand, Martin D.
关键词：
胰β细胞葡萄糖刺激胰岛素分泌（GSIS）受线粒体解偶联蛋白-2 （UCP2）调节，但不同UCP2消融小鼠模型中存在相反的表型，即GSIS改善和损伤。通过测量有和没有UCP2的附着的INS-1E胰岛素瘤细胞的线粒体生物能量学，我们发现UCP2有助于质子泄漏，并减弱葡萄糖诱导的呼吸活性和氧化磷酸化偶联效率的升高。引人注目的是，在INS-1E细胞中，UCP2敲除后的GSIS改善被细胞渗透性抗氧化剂MnTMPyP完全抵消。与这一观察结果一致，UCP2在高葡萄糖水平下降低线粒体活性氧。我们得出结论，UCP2通过急性降低GSIS和慢性预防氧化应激在β细胞中发挥调节和保护作用。因此，我们的发现为该领域明显差异的发现提供了一种机制解释。
Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is regulated by mitochondrial uncoupling protein-2 (UCP2), but opposing phenotypes, GSIS improvement and impairment, have been reported for different Ucp2-ablated mouse models. By measuring mitochondrial bioenergetics in attached INS-1E insulinoma cells with and without UCP2, we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. Strikingly, the GSIS improvement seen upon UCP2 knockdown in INS-1E cells is annulled completely by the cell-permeative antioxidant MnTMPyP. Consistent with this observation, UCP2 lowers mitochondrial reactive oxygen species at high glucose levels. We conclude that UCP2 plays both regulatory and protective roles in β cells by acutely lowering GSIS and chronically preventing oxidative stress. Our findings thus provide a mechanistic explanation for the apparently discrepant findings in the field.
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