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

Research output: Contribution to journalArticlepeer-review

6 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 languageEnglish
Pages (from-to)48-61.e6
JournalCell Metabolism
Volume36
Issue number1
DOIs
StatePublished - 2 Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

The study was supported by grants from the Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1250-S-B ), HIRN ( U01DK135001 ), NIDDK ( R01DK133442 ), The Alex U Soyka pancreatic cancer fund , The Israel Science Foundation , and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research grant in Heart studies . The study was also supported by the Human Islet Research Network (RRID: SCR_014393 ), the Human Pancreas Analysis Program (RRID: SCR_016202 ), DK133442 , DK106755 , DK123716 , DK117147 , DK112217 , DK20593 ( Vanderbilt Diabetes Research and Training Center ), The Leona M. and Harry B. Helmsley Charitable Trust , and the Department of Veterans Affairs ( BX000666 ). This study used human pancreatic islets that were provided by the NIDDK-Funded Integrated Islet Distribution Program at the City of Hope (DK098085). The study was supported by grants from the Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1250-S-B), HIRN (U01DK135001), NIDDK (R01DK133442), The Alex U Soyka pancreatic cancer fund, The Israel Science Foundation, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research grant in Heart studies. The study was also supported by the Human Islet Research Network (RRID:SCR_014393), the Human Pancreas Analysis Program (RRID:SCR_016202), DK133442, DK106755, DK123716, DK117147, DK112217, DK20593 (Vanderbilt Diabetes Research and Training Center), The Leona M. and Harry B. Helmsley Charitable Trust, and the Department of Veterans Affairs (BX000666). Conceptualization, Y.D. A.K. E.Y.L. C.D. and A.C.P.; investigation, U.E.K. S.P. A.K. C.D. R.C.-F. S.J. K.P. M.I. and L.Z.; writing and editing, A.K. Y.D. B.G. E.Y.L. C.D. and A.C.P.; review & editing, all authors; supervision, Y.D. A.K. E.Y.L. and A.C.P.; funding, Y.D. A.C.P. and E.Y.L. The authors declare no competing interests.

FundersFunder number
Alex U Soyka Pancreatic Cancer Fund
NIDDK-FundedDK098085
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK133442
U.S. Department of Veterans AffairsBX000666
Juvenile Diabetes Research Foundation International2-SRA-2022-1250-S-B
Leona M. and Harry B. Helmsley Charitable Trust
Human Islet Research NetworkU01DK135001
Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center
Israel Science Foundation
Stichting Diabetes Onderzoek NederlandDK20593, SCR_016202, DK112217, DK117147, DK123716, DK106755, SCR_014393

    Keywords

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

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