| First Author | Horwitz E | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 11 | Pages | 2305-2318 |
| PubMed ID | 30150306 | Mgi Jnum | J:266082 |
| Mgi Id | MGI:6208511 | Doi | 10.2337/db17-1006 |
| Citation | Horwitz E, et al. (2018) beta-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes. Diabetes 67(11):2305-2318 |
| abstractText | Type 1 diabetes (T1D) is an autoimmune disease where pancreatic beta-cells are destroyed by islet-infiltrating T cells. Although 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 patients with recently diagnosed T1D 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, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1beta and Cxcl10. beta-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 beta-cell DDR is an early event in T1D, possibly contributing to autoimmunity. |
