Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood nerve barrier (BNB). While non-lesioned fascicles from T2D donors showed activation of neuroprotective pathways, lesioned fascicles lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful inter-organ communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.

中文翻译：

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探索糖尿病神经病变坐骨神经病变的结构和分子特征：揭示致病途径和靶点


糖尿病神经病变 （DN） 个体坐骨神经中的病变束 （LF） 与临床症状严重程度相关。本研究旨在表征这些病变的结构和分子组成，以更好地了解 DN 的发病机制。使用离体磁共振神经造影、体外成像和蛋白质组学分析检查患有和不患有 2 型糖尿病 （T2D） 的截肢者的坐骨神经。病变仅在 T2D 供体中发现，并表现出显着的结构异常，包括轴突变性、脱髓鞘和血神经屏障受损 （BNB）。虽然来自 T2D 供体的非损伤束表现出神经保护性通路的激活，但损伤束缺乏这种反应，而是通过经典通路表现出补体激活增加。肝源性急性期蛋白的检测表明 BNB 破坏促进了肝脏和神经之间有害的器官间通讯。这些发现揭示了导致 DN 的关键分子机制，并突出了治疗干预的潜在靶点。