Disrupted RNA editing in beta cells mimics early-stage type 1 diabetes
Udi Ehud Knebel, Shani Peleg, Chunhua Dai, Roni Cohen‐Fultheim, Sara Jönsson, Karin Poznyak, Maya Israeli, Liza Zamashanski, Benjamin Gläser, Erez Y. Levanon, Alvin C. Powers, Agnes Klochendler, Yuval Dor
Abstract
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.