Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function. Function (Oxf) 2022;3(4):zqac034
Date
07/26/2022Pubmed ID
35873655Pubmed Central ID
PMC9301323DOI
10.1093/function/zqac034Scopus ID
2-s2.0-85138214139 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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 depletion, 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.
Author List
Stancill JS, Hansen PA, Mathison AJ, Schmidt EE, Corbett JAAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinAngela Mathison PhD Associate Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Glucose
Homeostasis
Mice
Mice, Knockout
NF-E2-Related Factor 2
Oxidation-Reduction
Reactive Oxygen Species
