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

Area of Science:

• Cellular biology
• Endocrinology
• Oxidative stress research

Background:

• Reactive oxygen species (ROS) contribute to pancreatic beta-cell damage.
• Thioredoxin reductase (Txnrd), thioredoxin, and peroxiredoxins are key antioxidant defenses in beta-cells.
• The in vivo role of this antioxidant cycle in beta-cell redox homeostasis and survival is not fully understood.

Purpose of the Study:

• To investigate the role of thioredoxin reductase 1 (Txnrd1) in maintaining beta-cell function and survival in vivo.
• To determine the adaptive responses of beta-cells lacking Txnrd1.

Main Methods:

• Generation of mice with a beta-cell specific knockout of Txnrd1 (βKO).
• Assessment of glucose homeostasis and glucose-stimulated insulin secretion.
• Analysis of ROS sensitivity in knockout islets.
• RNA-sequencing to analyze gene expression changes in Txnrd1-deficient beta-cells.

Main Results:

• Txnrd1 knockout mice maintained normal whole-body glucose homeostasis despite blunted insulin secretion.
• Txnrd1-deficient beta-cells showed no increased sensitivity to ROS.
• RNA-sequencing revealed increased expression of Nrf2-regulated genes and altered heme/glutathione metabolism genes.
• A decrease in factors controlling beta-cell function and identity was observed in knockout beta-cells.

Conclusions:

• Beta-cell specific loss of Txnrd1 triggers an adaptive response involving Nrf2-regulated antioxidant genes.
• This compensation protects beta-cells from ROS but comes at the cost of impaired beta-cell function and identity.
• Txnrd1 is essential for maintaining both antioxidant defense and normal function in pancreatic beta-cells.