Oxidative stress and beta-cell dysfunction
Oxidative stress and beta-cell dysfunction
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DOI：
10.1007/s00424-010-0862-9
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发表时间：
2010-09-01
影响因子：
4.5
通讯作者：
Duefer, Martina
中科院分区：
文献类型：
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作者：
Drews, Gisela;Krippeit-Drews, Peter;Duefer, Martina
1型和2型糖尿病（T1DM和T2DM）是复杂的多因素疾病。由分泌能力降低和细胞凋亡增强引起的β细胞功能丧失是两种糖尿病类型发病机制中的关键事件。由活性氧和氮物质诱导的氧化应激在糖尿病发展期间严重参与β细胞功能的损害。由于它们的抗氧化能力低，β细胞对氧化应激非常敏感。在β细胞中，氧化剂损伤的重要靶点是细胞代谢和K（ATP）通道。氧化剂诱发的K（ATP）通道活性改变似乎对氧化剂诱导的功能障碍至关重要，因为K（ATP）通道的遗传消融减弱了氧化应激对β细胞功能的影响。除了对代谢的影响外，氧化剂对线粒体的干扰诱导细胞凋亡的关键事件。因此，增加抗氧化防御是一种有前途的策略，以延迟（前）糖尿病患者或胰岛移植期间的β细胞衰竭。K（ATP）通道的敲除对氧化剂诱导的胰岛素分泌抑制和细胞死亡具有有益作用。有趣的是，这些作用可以通过磺酰脲类药物模拟，这些药物已用于治疗T2DM多年。功能性K（ATP）通道的丧失导致抗氧化酶的上调，这是一个依赖于胞质Ca（2+）的过程。这些观察结果对于临床干预非常重要，因为它们显示了在分泌能力的显著变化和细胞质量的损失变得明显并导致葡萄糖耐受不良或甚至明显的糖尿病之前的早期阶段保护β细胞的可能性。
Diabetes mellitus type 1 and 2 (T1DM and T2DM) are complex multifactorial diseases. Loss of beta-cell function caused by reduced secretory capacity and enhanced apoptosis is a key event in the pathogenesis of both diabetes types. Oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during the development of diabetes. Because of their low antioxidant capacity, beta-cells are extremely sensitive towards oxidative stress. In beta-cells, important targets for an oxidant insult are cell metabolism and K(ATP) channels. The oxidant-evoked alterations of K(ATP) channel activity seem to be critical for oxidant-induced dysfunction because genetic ablation of K(ATP) channels attenuates the effects of oxidative stress on beta-cell function. Besides the effects on metabolism, interference of oxidants with mitochondria induces key events in apoptosis. Consequently, increasing antioxidant defence is a promising strategy to delay beta cell failure in (pre)-diabetic patients or during islet transplantation. Knock-out of K(ATP) channels has beneficial effects on oxidant-induced inhibition of insulin secretion and cell death. Interestingly, these effects can be mimicked by sulfonylureas that have been used in the treatment of T2DM for many years. Loss of functional K(ATP) channels leads to up-regulation of antioxidant enzymes, a process that depends on cytosolic Ca(2+). These observations are of great importance for clinical intervention because they show a possibility to protect beta-cells at an early stage before dramatic changes of the secretory capacity and loss of cell mass become manifest and lead to glucose intolerance or even overt diabetes.