We next explored the physiological connection of TXNIP to ER stress-mediated cell degeneration and disease. Given that the loss of TXNIP protects against glucotoxicity, we tested whether it would similarly protect cells against ER stress-induced programmed cell death. To this end, we challenged Txnip−/− MEFs with ER stress agents and found that they are strikingly resistant to programmed cell death (Figure 4A), despite the fact that adaptive UPR outputs—XBP1 mRNA splicing and transcriptional induction of the ER chaperone BiP—are no different than in Txnip+/+ MEFs (Figure S6A and B). As with cell lines, freshly harvested pancreatic islets from wild-type C57BL/6 mice induce TXNIP mRNA under Tm (Figure 4B). However, β-cells in pancreatic islets from Txnip−/− mice are strongly protected (compared to Txnip+/+ mice) from programmed cell death under Tm (Figure 4C and D).
