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 | |
| State | Published - 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.
| Funders | Funder number |
|---|---|
| Alex U Soyka Pancreatic Cancer Fund | |
| NIDDK-Funded | DK098085 |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01DK133442 |
| U.S. Department of Veterans Affairs | BX000666 |
| Juvenile Diabetes Research Foundation International | 2-SRA-2022-1250-S-B |
| Leona M. and Harry B. Helmsley Charitable Trust | |
| Human Islet Research Network | U01DK135001 |
| Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center | |
| Israel Science Foundation | |
| Stichting Diabetes Onderzoek Nederland | DK20593, SCR_016202, DK112217, DK117147, DK123716, DK106755, SCR_014393 |
Keywords
- RNA editing
- beta cells
- interferon response
- islet inflammation
- metabolic stress
- type 1 diabetes
