Type 1 diabetes (T1D) is an autoimmune disease where pancreatic b-cells are destroyed by islet-infiltrating T cells. Although a role for b-cell defects has been suspected, b-cell abnormalities are difficult to demonstrate. We show a b-cell DNA damage response (DDR), presented by activation of the 53BP1 protein and accumulation of p53, in biopsy and autopsy material from patients with recently diagnosed T1D as well as a rat model of human T1D. The b-cell DDR is more frequent in islets infiltrated by CD45+ immune cells, suggesting a link to islet inflammation. The b-cell toxin streptozotocin (STZ) elicits DDR in islets, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1b and Cxcl10. b-Cell-specific inactivation of the master DNA repair gene ataxia telangiectasia mutated (ATM) in STZ-treated mice decreases the expression of proinflammatory cytokines in islets and attenuates the development of hyperglycemia. Together, these data suggest that b-cell DDR is an early event in T1D, possibly contributing to autoimmunity.
Bibliographical noteFunding Information:
Funding. The DiViD project was funded by the South-Eastern Norway Regional Health Authority (grant to K.D.-J.), by the Novo Nordisk Foundation (grant to K.D.-J.), and through the Persistent Virus Infection in Diabetes Network (PEVNET) Study Group funded by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement 261441 PEVNET. This research also was performed with the support of nPOD, a collaborative T1D research project sponsored by JDRF International. Organ procurement organizations partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. Y.D. is supported by grants from JDRF, the Human Islet Research Network of the National Institutes of Health (DK-104216), The Leona M. and Harry B. Helmsley Charitable Trust, the European Union (project ELASTISLET), Britain Israel Research and Academic Exchange, the Israel Science Foundation, the DON Foundation, and by a pilot grant from The Leona M. and Harry B. Helmsley Charitable Trust George S. Eisenbarth nPOD Award for Team Science (to Y.D.). Work in the A.C.P. laboratory at Vanderbilt University was supported by grants from the National Institutes of Health (DK-89572, DK-104211, DK-108120, DK-106755, and DK-20593), JDRF, and Department of Veterans Affairs. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. E.H., S.Z., A.S., M.F., T.L., T.D., N.H., N.W.-C., and A.K. performed experiments. E.H., A.S., A.K., B.G., and Y.D. wrote the manuscript. E.H., B.G., and Y.D. designed the study. L.K., A.C.P., M.B., and K.D.-J. contributed human material. A.J. and S.L. contributed rat material. E.H. and Y.D. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
© 2018 by the American Diabetes Association.