Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus.
Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus.
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DOI：
10.1155/2012/703538
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发表时间：
2012
影响因子：
--
通讯作者：
Turk J
中科院分区：
文献类型：
--
作者：
Ma ZA;Zhao Z;Turk J
2型糖尿病（T2DM）是人类最常见的内分泌疾病，以外周胰岛素抵抗和胰岛β细胞衰竭为特征。越来越多的证据表明，线粒体功能障碍是2型糖尿病演变过程中β细胞衰竭的主要因素。如前所述，代谢应激导致β细胞线粒体产生的活性氧（ROS）激活了几种应激反应途径。本文主要探讨活性氧影响线粒体结构和功能并导致β细胞衰竭的机制。ROS激活UCP2，导致质子渗漏穿过线粒体内膜，从而导致β细胞ATP合成和含量降低，而ATP是调节葡萄糖刺激胰岛素分泌的关键参数。此外，ROS氧化线粒体心磷脂和其他磷脂中的多不饱和脂肪酸，从而损害细胞膜的完整性，导致细胞色素c释放到细胞质中并导致细胞凋亡。VIA组磷脂酶A2 （iPLA2 β）似乎是修复含有氧化脂肪酸取代基的线粒体磷脂机制的一个组成部分，遗传或获得性iPLA2 β缺乏增加β细胞线粒体对ROS损伤的易感性，并易患T2DM。干预措施减弱ROS对β细胞线粒体磷脂的影响可能预防或延缓T2DM的发展。
Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead to β-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochrome c release into cytosol and apoptosis. Group VIA phospholipase A2 (iPLA2 β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA2 β-deficiency increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM.
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