Diabetes‐associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and ultimately fibrosis. Carbohydrates were found to trigger this cascade by decreasing the NAD ⁺/NADH ratio and NHEJ ‐repair in vitro and in diabetes mouse models. Restoring DNA repair by nuclear over‐expression of phosphomimetic RAGE reduces DNA damage, inflammation, and fibrosis, thereby restoring organ function. Our study provides a novel conceptual framework for understanding diabetic fibrosis on the basis of persistent DNA damage signaling and points to unprecedented approaches to restore DNA repair capacity for resolution of fibrosis in patients with diabetes.

中文翻译：

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受损的 DNA 修复是糖尿病相关纤维化的原因。

以细胞衰老升高为特征的糖尿病相关器官纤维化是一个日益严重的健康问题。有趣的是，这种关联背后的机制仍然未知。此外，单独使用胰岛素既不能逆转器官纤维化，也不能逆转相关的分泌表型，这支持了一个令人兴奋的观点，即迄今为止未知的机制必须起作用。在这里，我们表明实验性 1 型和 2 型糖尿病会损害 DNA 修复，导致衰老、炎症表型和最终纤维化。发现碳水化合物通过降低 NAD ^{+ /NADH 比率和}体外NHEJ 修复来触发这种级联反应在糖尿病小鼠模型中。通过拟磷化 RAGE 的核过表达来恢复 DNA 修复可减少 DNA 损伤、炎症和纤维化，从而恢复器官功能。我们的研究为基于持续性 DNA 损伤信号传导理解糖尿病纤维化提供了一个新的概念框架，并指出了前所未有的方法来恢复 DNA 修复能力以解决糖尿病患者的纤维化。