Disrupted RNA editing in beta cells mimics early-stage type 1 diabetes
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 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. Overall design: Inactivation of Adar in pancreatic beta-cells from young adult mice (MipCreER; Adar floxed/floxed) causes insulitis and diabetes. To understand the molecular basis for islet inflammation, we have performed RNA-Sequencing on FACS-sorted beta-cells isolated from beta-cell specific Adar -Knockout (betaAdarKO) and control beta-cell specific Adar-heterozygotes (betaAdarHET) (n=4 for each genotype). We then profiled and compared gene expression from RNA-Seq data of AdarKO and AdarHET beta-cells