| First Author | Herlea-Pana O | Year | 2021 |
| Journal | Front Endocrinol (Lausanne) | Volume | 12 |
| Pages | 749879 | PubMed ID | 34675883 |
| Mgi Jnum | J:312477 | Mgi Id | MGI:6785433 |
| Doi | 10.3389/fendo.2021.749879 | Citation | Herlea-Pana O, et al. (2021) Pharmacological Inhibition of Inositol-Requiring Enzyme 1alpha RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes. Front Endocrinol (Lausanne) 12:749879 |
| abstractText | beta-cell ER stress plays an important role in beta-cell dysfunction and death during the pathogenesis of diabetes. Proinsulin misfolding is regarded as one of the primary initiating factors of ER stress and unfolded protein response (UPR) activation in beta-cells. Here, we found that the ER stress sensor inositol-requiring enzyme 1alpha (IRE1alpha) was activated in the Akita mice, a mouse model of mutant insulin gene-induced diabetes of youth (MIDY), a monogenic diabetes. Normalization of IRE1alpha 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 IRE1alpha RNase inhibitors. This study provides the evidence of the in vivo efficacy of IRE1alpha RNase inhibitors in Akita mice, pointing to the possibility of targeting IRE1alpha RNase as a therapeutic direction for the treatment of diabetes. |
