Disrupted RNA editing in beta cells mimics early-stage type 1 diabetes

• DOI: 10.1016/j.cmet.2023.11.011
• Publication Date: 2023-12-20T15:27:25Z
• Authors: Udi Ehud Knebel; Shani Peleg; Chunhua Dai; Roni Cohen-Fultheim; Sara Jonsson; Karin Poznyak; Maya Israeli; Liza Zamashanski; Benjamin Glaser; Erez Y. Levanon; Alvin C. Powers; Agnes Klochendler; Yuval Dor
• Keywords: Inflammation; Mice; Diabetes Mellitus, Type 1; Animals; Humans; RNA Editing; Interferons; RNA, Double-Stranded

A major hypothesis for the etiology of type 1 diabetes (T1D) postulates initiation by viral infection, leading to double-stranded RNA (dsRNA)-mediated interferon response and inflammation; however, a causal virus has not been identified. Here, we use a mouse model, corroborated with human islet data, to demonstrate that endogenous dsRNA in beta cells can lead to a diabetogenic immune response, thus identifying a virus-independent mechanism for T1D initiation. We found that disruption of the RNA editing enzyme adenosine deaminases acting on RNA (ADAR) in beta cells triggers a massive interferon response, islet inflammation, and beta cell failure and destruction, with features bearing striking similarity to early-stage human T1D. Glycolysis via calcium enhances the interferon response, suggesting an actionable vicious cycle of inflammation and increased beta cell workload.