Inhibition of inositol-requiring enzyme 1 RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes

Proinsulin misfolding in the endoplasmic reticulum (ER) plays an important role in {beta}-cell dysfunction and death and the pathogenesis of mutant INS-gene-induced diabetes of youth (MIDY). There is no effective treatment for MIDY except the insulin administration. Here, we found that the ER stress sensor inositol-requiring enzyme 1 (IRE1) was activated in the Akita mice, a mouse model of MIDY. Normalization of IRE1 RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional {beta}-cell mass, as shown by the suppression of {beta}-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with {beta}-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1 RNase inhibitors. This study provides the first evidence of the in vivo efficacy of IRE1 RNase inhibition in Akita mice, pointing to the possibility of targeting IRE1 RNase as a therapeutic direction for the treatment of MIDY diabetes.