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

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

doi:10.1016/j.cmet.2023.11.011

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

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^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Pages (from-to)	48-61.e6
Journal	Cell Metabolism
Volume	36
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2023.11.011
State	Published - 2 Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

RNA editing
beta cells
interferon response
islet inflammation
metabolic stress
type 1 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2023.11.011

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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.",

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AU - Jonsson, Sara

AU - Poznyak, Karin

AU - Israeli, Maya

AU - Zamashanski, Liza

AU - Glaser, Benjamin

AU - Levanon, Erez Y.

AU - Powers, Alvin C.

AU - Klochendler, Agnes

AU - Dor, Yuval

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AB - 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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KW - interferon response

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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