The Role of Thioredoxin/Peroxiredoxin in the β-Cell Defense Against Oxidative Damage

Stancill, Jennifer S.; Corbett, John A.

doi:10.3389/fendo.2021.718235

Cited by 37 publications

(16 citation statements)

References 80 publications

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“…Together, previous studies and the work presented here suggest that TrxR plays at least two critical roles in pancreatic β-cells. 88 First, TrxR1 is necessary for β-cell protection against ROS, as evidenced by increased sensitivity to oxidative damage when Txnrd1 is inactivated 28 , 31 and by upregulation of a number of cytoprotective genes to maintain survival when Txnrd1 is depleted (current study). Second, TrxR1 is necessary for normal β-cell function and maturation, as evidenced by impaired glucose-stimulated insulin secretion when Txnrd1 is inhibited or knocked out and by decreased expression of β-cell maturation markers when Txnrd1 is chronically depleted (current study).…”

Section: Discussionmentioning

confidence: 83%

Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function

et al. 2022

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Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletions, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1fl/fl; Ins1Cre/+, βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.

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Section: Discussionmentioning

confidence: 83%

Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function

et al. 2022

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“…Accordingly, in metformin-treated islets, we also found a significantly increased expression of proteins involved in the defense against oxidative stress [ 71 , 72 ], such as glutathione S-transferase α1 and 2 (GSTA1 and 2); thioredoxin 1 (TRX1); and peroxiredoxins 2, 3, and 5 (PRDX2, 3, and 5). The peroxiredoxin/thioredoxin antioxidant system has been described in rodent β-cell lines and pancreatic islets as a relevant protective mechanism against oxidative damage [ 73 , 74 , 75 , 76 ]. The specific role of each peroxiredoxin is still debated.…”

Section: Discussionmentioning

confidence: 99%

The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved

Giusti

Tesi

Ciregia

et al. 2022

Cells

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Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.

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“…Peroxiredoxin catalyzes the reduction of H 2 O 2 to water, and oxidized peroxiredoxin is reduced by thioredoxin that, in turn, becomes oxidized. Oxidized thioredoxin is reduced by thioredoxin reductase using NADPH [ 54 ]. Peroxiredoxin and thioredoxin are important for redox signaling and are part of the first line of defense against H 2 O 2 .…”

Section: Ros Generation and Antioxidant Defense In β-Cellsmentioning

confidence: 99%

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

2022

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The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells.

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The Role of Thioredoxin/Peroxiredoxin in the β-Cell Defense Against Oxidative Damage

Cited by 37 publications

References 80 publications

Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function

Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function

The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

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