323-LB: Activation of the GLP-1 Receptor Signaling Prevents Beta-Cell Dedifferentiation in a Mouse Model of Wolfram Syndrome through Modulating TXNIP Expression

Abstract

Loss of functional β cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. Currently, there are no specific treatment recommendations for the disease. We have so far evidenced that, in the Wfs1-/- mice, β cells become dedifferentiated and revert to endocrine progenitor-like cells expressing Ngn3, and a subset of β cells takes α cell fate. Such β cell plasticity appears after nursing, independently of hyperglycaemia, and becomes more apparent along with diabetes progression accompanied with no significant increase in apoptosis. In this study, we examined the potential effects of a GLP-1 receptor agonist on β cell plasticity and glucose homeostasis in young Wfs1−/− mice without noticeable hyperglycaemia. Results: Four weeks administration of Ex-4 resulted in an off-drug amelioration of glucose excursions after glucose loading in Wfs1−/− mice, with insulin secretory dynamics that were indistinguishable from those in WT mice, despite no alteration in beta cell mass. In association with the functional improvements, Ex-4 alleviated β cell dedifferentiation evidenced by a decrease of MafA and a Ngn3 emergence. At the same time, Ex-4 reversed a robust increase in thioredoxin interacting protein (TXNIP) in Wfs1-/- β cells. Mechanistically, Ex-4 suppressed it at both transcriptional and post-translational levels. Furthermore, we have found that genetic ablation of Txnip in Wfs1-/- mice inhibited β cell dedifferentiation, resulting in prevention of diabetes progression with preservation of β cell mass. Our finding implies that activation of the GLP-1 receptor signaling may prevent β cells from becoming dedifferentiated by modulating Txnip and may slow diabetes progression in Wolfram syndrome. Disclosure K. Tanabe: None. K. Amo-Shiinoki: None. M. Hatanaka: None. Y. Tanizawa: None. Funding Japan Society for the Promotion of Science (16K09752, 15K21198, 15K09390); Japan Diabetes Society; Japan Association for Diabetes Education and Care