Beta Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease, where pancreatic beta-cells are destroyed by islet infiltrating T-cells. While a role for beta-cell defects has been suspected, beta-cell abnormalities are difficult to demonstrate. We show a beta-cell DNA damage response (DDR), presented by activation of the 53BP1 protein and accumulation of p53, in biopsy and autopsy material from recently diagnosed T1D patients as well as a rat model of human T1D. The beta-cell DDR is more frequent in islets infiltrated by CD45+ immune cells, suggesting a link to islet inflammation. The beta-cell toxin streptozotocin (STZ) elicits DDR in islets, in vivo and ex vivo, and causes elevation of the pro-inflammatory molecules IL-1β and Cxcl10. Beta-cell specific inactivation of the master DNA repair gene Ataxia Telangiectasia Mutated (ATM) in STZ-treated mice decreases the expression of pro-inflammatory cytokines in islets and attenuates the development of hyperglycemia. Together, these data suggest that beta-cell DDR is an early event in T1D, possibly contributing to autoimmunity.