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Diabetes. 2018 Nov;67(11):2305-2318. doi: 10.2337/db17-1006. Epub 2018 Aug 27.

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

Author information

1
Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel.
2
Paediatric Department, Oslo University Hospital HF, Faculty of Medicine, University of Oslo, Oslo, Norway.
3
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
4
Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN.
5
Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
6
Institute of Experimental Diabetes Research and Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
7
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
8
Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel yuvald@ekmd.huji.ac.il knut.dahl-jorgensen@medisin.uio.no.

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.

PMID:
30150306
PMCID:
PMC6198335
[Available on 2019-11-01]
DOI:
10.2337/db17-1006
[Indexed for MEDLINE]

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