Diabetic peripheral neuropathy (DPN) is a highly frequent and debilitating clinical complication of diabetes that lacks therapies. Cellular oxidative stress regulates post-translational modifications, including SUMOylation. Here, using unbiased screens, we identified key enzymes in metabolic pathways and ion channels as novel molecular targets of SUMOylation that critically regulated their activity. Sensory neurons of diabetic patients and diabetic mice demonstrated changes in the SUMOylation status of metabolic enzymes and ion channels. In support of this, profound metabolic dysfunction, accelerated neuropathology, and sensory loss were observed in diabetic gene-targeted mice selectively lacking the ability to SUMOylate proteins in peripheral sensory neurons. TRPV1 function was impaired by diabetes-induced de-SUMOylation as well as by metabolic imbalance elicited by de-SUMOylation of metabolic enzymes, facilitating diabetic sensory loss. Our results unexpectedly uncover an endogenous post-translational mechanism regulating diabetic neuropathy in patients and mouse models that protects against metabolic dysfunction, nerve damage, and altered sensory perception.

糖尿病周围神经病变（DPN）是缺乏治疗方法的糖尿病的高度频繁且使人衰弱的临床并发症。细胞氧化应激调节翻译后修饰，包括SUMOylation。在这里，使用无偏筛选，我们确定了代谢途径和离子通道中的关键酶是SUMOylation的新型分子靶标，可严格调节其活性。糖尿病患者和糖尿病小鼠的感觉神经元显示出代谢酶和离子通道的SUMOylation状态发生了变化。为此，在选择性缺乏对周围感觉神经元蛋白质进行SUMOylate处理能力的糖尿病基因靶向小鼠中观察到了严重的代谢功能障碍，神经病理学加速和感觉丧失。糖尿病诱导的脱SUMOylation以及代谢酶脱SUMOylation引起的代谢失衡会损害TRPV1的功能，从而促进糖尿病感官的丧失。我们的结果出乎意料地揭示了调节患者和小鼠模型中糖尿病神经病的内源性翻译后机制，该机制可防止代谢功能障碍，神经损伤和感觉知觉改变。