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Pancreatic ?-cells detoxify H₂O₂ through the peroxiredoxin/thioredoxin antioxidant system.

ABSTRACT: Oxidative stress is thought to promote pancreatic ?-cell dysfunction and contribute to both type 1 and type 2 diabetes. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, are mediators of oxidative stress that arise largely from electron leakage during oxidative phosphorylation. Reports that ?-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which ?-cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of ?-cells in the control of metabolic homeostasis and organismal survival through exquisite coupling of oxidative phosphorylation, a prominent ROS-producing pathway, to insulin secretion. Using glucose oxidase to deliver H₂O₂ continuously over time and Amplex Red to measure extracellular H₂O₂ concentration, we found here that ?-cells can remove micromolar levels of this oxidant. This detoxification pathway utilizes the peroxiredoxin/thioredoxin antioxidant system, as selective chemical inhibition or siRNA-mediated depletion of thioredoxin reductase sensitized ?-cells to continuously generated H₂O₂ In contrast, when delivered as a bolus, H₂O₂ induced the DNA damage response, depleted cellular energy stores, and decreased ?-cell viability independently of thioredoxin reductase inhibition. These findings show that ?-cells have the capacity to detoxify micromolar levels of H₂O₂ through a thioredoxin reductase-dependent mechanism and are not as sensitive to oxidative damage as previously thought.

SUBMITTER: Stancill JS

PROVIDER: S-EPMC6442057 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Pancreatic β-cells detoxify H<sub>2</sub>O<sub>2</sub> through the peroxiredoxin/thioredoxin antioxidant system.

Stancill Jennifer S JS Broniowska Katarzyna A KA Oleson Bryndon J BJ Naatz Aaron A Corbett John A JA

The Journal of biological chemistry 20190118 13

Oxidative stress is thought to promote pancreatic β-cell dysfunction and contribute to both type 1 and type 2 diabetes. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, are mediators of oxidative stress that arise largely from electron leakage during oxidative phosphorylation. Reports that β-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which β-cells are ill-equipped to detoxify ROS. This hypothesis seem ...[more]

PMID: 30659092

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Project description:Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes.

Dataset Information

Pancreatic ?-cells detoxify H₂O₂ through the peroxiredoxin/thioredoxin antioxidant system.

Publications

Pancreatic β-cells detoxify H<sub>2</sub>O<sub>2</sub> through the peroxiredoxin/thioredoxin antioxidant system.

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Pancreatic ?-cells detoxify H2O2 through the peroxiredoxin/thioredoxin antioxidant system.

Publications

Pancreatic β-cells detoxify H<sub>2</sub>O<sub>2</sub> through the peroxiredoxin/thioredoxin antioxidant system.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Pancreatic ?-cells detoxify H₂O₂ through the peroxiredoxin/thioredoxin antioxidant system.