| First Author | Amo-Shiinoki K | Year | 2025 |
| Journal | Sci Transl Med | Volume | 17 |
| Issue | 786 | Pages | eadp2332 |
| PubMed ID | 39970233 | Mgi Jnum | J:363378 |
| Mgi Id | MGI:7868573 | Doi | 10.1126/scitranslmed.adp2332 |
| Citation | Amo-Shiinoki K, et al. (2025) beta cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome. Sci Transl Med 17(786):eadp2332 |
| abstractText | Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by WFS1 gene mutations. However, the pathological process of ER stress-associated beta cell failure remains to be fully elucidated. Our results indicate loss of beta cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of beta cells and subsequent decrease in alpha cells, suggesting loss of endocrine function. Wfs1-deficient mice displayed dysfunction, gradual loss, and dedifferentiation of beta cells, leading to permanent hyperglycemia. Impairment of the beta cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced beta cells. Islets of Wfs1-deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, Wfs1-null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS beta cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress-induced protein up-regulated in Wfs1 deficiency. Txnip deletion preserved functional beta cells and prevented diabetes progression in Wfs1-deficient mice. Together, this study deciphered pathological mechanisms of beta cell dedifferentiation in beta cell failure and has implications for Txnip inhibition in WS therapy. |
