Abstract
Oxidative stress is hypothesized to play a role in pancreatic β-cell damage, potentially contributing to β-cell dysfunction and death in both type 1 and type 2 diabetes. Oxidative stress arises when naturally occurring reactive oxygen species (ROS) are produced at levels that overwhelm the antioxidant capacity of the cell. ROS, including superoxide and hydrogen peroxide, are primarily produced by electron leak during mitochondrial oxidative metabolism. Additionally, peroxynitrite, an oxidant generated by the reaction of superoxide and nitric oxide, may also cause β-cell damage during autoimmune destruction of these cells. β-cells are thought to be susceptible to oxidative damage based on reports that they express low levels of antioxidant enzymes compared to other tissues. Furthermore, markers of oxidative damage are observed in islets from diabetic rodent models and human patients. However, recent studies have demonstrated high expression of various isoforms of peroxiredoxins, thioredoxin, and thioredoxin reductase in β-cells and have provided experimental evidence supporting a role for these enzymes in promoting β-cell function and survival in response to a variety of oxidative stressors. This mini-review will focus on the mechanism by which thioredoxins and peroxiredoxins detoxify ROS and on the protective roles of these enzymes in β-cells. Additionally, we speculate about the role of this antioxidant system in promoting insulin secretion.
Highlights
Diabetes mellitus, affecting 29.1 million people in the United States [1], is a group of diseases characterized by high blood glucose, or hyperglycemia, and is caused by failure of pancreatic b-cells to secrete sufficient insulin to match the requirements of the body
The studies reviewed above collectively indicate that, while bcells have low activity of catalase and glutathione peroxidase compared to other tissues [14, 16, 40], they maintain a robust antioxidant system primarily requiring the cytoplasmic thioredoxin reductase 1 (TXNRD1), thioredoxin 1 (TXN1), and peroxiredoxin 1 (PRDX1)
NAPDH for this system is provided in the cytoplasm by glucose-6 phosphate dehydrogenase (G6PD)
Summary
Diabetes mellitus, affecting 29.1 million people in the United States [1], is a group of diseases characterized by high blood glucose, or hyperglycemia, and is caused by failure of pancreatic b-cells to secrete sufficient insulin to match the requirements of the body. Superoxide can be produced via NADPH oxidases, which catalyze the addition of an electron (using NADPH) to molecular oxygen [35] This is another mechanism by which inflammatory cytokines may generate ROS in b-cells [36,37,38]. Hydrogen peroxide can be generated from superoxide by spontaneous dismutation or through a reaction catalyzed by superoxide dismutase (SOD) [39] It can either undergo the Fenton Reaction, reacting with free iron or copper ions to form the highly reactive hydroxyl radical (OH), or it can be reduced to water by several different antioxidants, including catalase, glutathione peroxidase, or peroxiredoxin [39]. Peroxynitrite (ONOO-) is a reactive species generated by the diffusion-controlled reaction of superoxide and nitric oxide and has been suggested to contribute to b-cell damage in response to pro-inflammatory cytokines [41, 42]. When b-cells are forced to generate peroxynitrite by providing exogenous superoxide and nitric oxide, superoxide scavenges the nitric oxide, forming peroxynitrite, and attenuates nitric oxide-mediated damage, suggesting that b-cells possess a robust mechanism to protect them from the damaging effects of peroxynitrite [43, 45, 46]
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