Division of Metabolism, Endocrinology and Nutrition, Department of Internal Medicine, University of Washington, Seattle, WA 98105, USA.
Int J Mol Sci. 2023 Feb 4;24(4):3082. doi: 10.3390/ijms24043082.
This perspective examines the proposition that chronically elevated blood glucose levels caused by type 2 diabetes (T2D) harm body tissues by locally generating reactive oxygen species (ROS). A feed-forward scenario is described in which the initial onset of defective beta cell function T2D becomes sustained and causes chronic elevations in blood glucose, which flood metabolic pathways throughout the body, giving rise to abnormally high local levels of ROS. Most cells can defend themselves via a full complement of antioxidant enzymes that are activated by ROS. However, the beta cell itself does not contain catalase or glutathione peroxidases and thereby runs a greater risk of ROS-induced damage. In this review, previously published experiments are revisited to examine the concept that chronic hyperglycemia can lead to oxidative stress in the beta cell, how this relates to the absence of beta cell glutathione peroxidase (GPx) activity, and whether this deficiency might be ameliorated by genetic enrichment of beta cell GPx and by oral antioxidants, including ebselen, a GPx mimetic.
这一观点考察了这样一种假设，即 2 型糖尿病（T2D）引起的慢性高血糖水平通过局部产生活性氧（ROS）对身体组织造成损害。描述了一个前馈场景，即最初出现的β细胞功能缺陷的 T2D 持续存在，并导致血糖持续升高，使全身代谢途径充满葡萄糖，导致异常高的局部 ROS 水平。大多数细胞可以通过全套抗氧化酶来保护自己，这些酶被 ROS 激活。然而，β细胞本身不含过氧化氢酶或谷胱甘肽过氧化物酶，因此更容易受到 ROS 诱导的损伤。在这篇综述中，重新审视了之前发表的实验，以检验慢性高血糖是否会导致β细胞中的氧化应激，这与β细胞谷胱甘肽过氧化物酶（GPx）活性缺失有何关联，以及通过β细胞 GPx 的基因富集和包括 ebselen 在内的口服抗氧化剂是否可以改善这种缺陷，后者是一种 GPx 模拟物。
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