Considering the substantial cytoprotection enjoyed by Txnip−/− MEFs and islets against pharmacological inducers of ER stress, we next tested whether loss of TXNIP would ameliorate β-cell degeneration and development of diabetes in the Ins2WT/C96Y—“Akita”—mouse. Because INS2 (C96Y) proinsulin cannot form a critical intramolecular disulfide bond needed to fold in the ER, it accumulates as a proteotoxin that causes ER stress-induced β-cell loss and spontaneous diabetes during infancy (Oyadomari et al., 2002; Ron, 2002). Ins2WT/C96Y mice begin developing hyperglycemia at approximately 3 weeks of age, but are not frankly diabetic and can still dispose of a glucose load by glucose tolerance test (GTT) (Figure S6E). However, even at 3 weeks, islets from Ins2WT/C96Y mice display significantly elevated baseline IRE1α activation (~ two-fold increased XBP1 mRNA splicing), documenting elevated ER stress prior to development of frank diabetes (Figure 5 A). Furthermore, the IRE1α-TXNIP pathway is also activated in islets from Ins2WT/C96Y mice at 3 weeks of age, as evidenced by significantly decreased miR-17 levels and elevated TXNIP mRNA expression at baseline (Figure 5 B and C).
