Key result
Disruption of the RNA editing enzyme ADAR in beta cells triggered a massive interferon response, islet inflammation, and beta cell destruction, mimicking early-stage human type 1 diabetes.
Why the study?
A major hypothesis postulates type 1 diabetes is initiated by viral infection via double-stranded RNA-mediated interferon response, but a causal virus has not been identified.
Endogenous double-stranded RNA in beta cells, resulting from disrupted RNA editing, can lead to a diabetogenic immune response, identifying a virus-independent mechanism for T1D initiation.
Highlights a novel virus-independent T1D trigger; leaves open its role in human beta-cell autoimmunity.
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.
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Knebel et al. (2023) studied Type 1 diabetes. Disruption of RNA editing enzyme ADAR in beta cells was evaluated on Interferon response, islet inflammation, and beta cell failure and destruction. Disruption of the RNA editing enzyme ADAR in beta cells triggered a massive interferon response, islet inflammation, and beta cell destruction, mimicking early-stage human type 1 diabetes.
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