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

Reactive oxygen species (ROS) have been implicated as mediators of pancreatic beta-cell damage. While beta-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 beta-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and beta-cell survival in vivo remains unclear. Here, we generated mice with a beta-cell specific knockout of thioredoxin reductase 1 (Txnrd1(fl/fl); Ins1(Cre/+), beta KO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole-body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, beta KO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient beta-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 beta-cells also have decreased expression of factors controlling beta-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout beta-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 beta-cell function and identity.