Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel.
Paediatric Department, Oslo University Hospital HF, Faculty of Medicine, University of Oslo, Oslo, Norway.
Diabetes. 2018 Nov;67(11):2305-2318. doi: 10.2337/db17-1006. Epub 2018 Aug 27.
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.
1 型糖尿病（T1D）是一种自身免疫性疾病，其中胰岛浸润的 T 细胞破坏胰腺β细胞。尽管已经怀疑β细胞缺陷起作用，但β细胞异常很难证明。我们在最近诊断为 T1D 的患者的活检和尸检材料以及人类 T1D 的大鼠模型中显示了β细胞 DNA 损伤反应（DDR），其表现为 53BP1 蛋白的激活和 p53 的积累。β细胞 DDR 在被 CD45 免疫细胞浸润的胰岛中更为常见，提示与胰岛炎症有关。β细胞毒素链脲佐菌素（STZ）在体内和体外均引起胰岛 DDR，并导致促炎分子 IL-1β 和 Cxcl10 的升高。在 STZ 处理的小鼠中，β细胞特异性敲除主 DNA 修复基因共济失调毛细血管扩张突变（ATM）可降低胰岛中促炎细胞因子的表达，并减轻高血糖的发展。总之，这些数据表明，β细胞 DDR 是 T1D 的早期事件，可能与自身免疫有关。
