β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes

Diabetes
Elad HorwitzYuval Dor

Abstract

Type 1 diabetes (T1D) is an autoimmune disease where pancreatic β-cells are destroyed by islet-infiltrating T cells. Although a role for β-cell defects has been suspected, β-cell abnormalities are difficult to demonstrate. We show a β-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 β-cell DDR is more frequent in islets infiltrated by CD45+ immune cells, suggesting a link to islet inflammation. The β-cell toxin streptozotocin (STZ) elicits DDR in islets, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1β and Cxcl10. β-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 β-cell DDR is an early event in T1D, possibly contributing to autoimmunity.

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Citations

Dec 19, 2019·Diabetes/metabolism Research and Reviews·Laura NigiGuido Sebastiani
May 1, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Paul J BelmonteVirginia Smith Shapiro
Aug 19, 2020·PloS One·Celina UhlemeyerBengt-Frederik Belgardt
Feb 11, 2020·Frontiers in Endocrinology·Shan WanXijie Yu
Mar 6, 2019·International Journal of Molecular Sciences·Nagendra VermaClaudio Talora
Aug 8, 2020·Cells·Ewa Gurgul-Convey
Dec 20, 2020·Biomolecules·Gabriel Brawerman, Peter J Thompson
Nov 15, 2020·Journal of Cellular and Molecular Medicine·Tian-Yuan WangYao Wang
Aug 5, 2021·Cell Reports·Blaz LupseAmin Ardestani

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