探索糖尿病性神经病变中坐骨神经损伤的结构和分子特征：揭示致病途径和靶点。

Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets.

作者信息

Schwarz Daniel, Le Marois Maxime, Sturm Volker, Peters Andreas S, Longuespée Rémi, Helm Dominic, Schneider Martin, Eichmüller Bastian, Hidmark Asa S, Fischer Manuel, Kender Zoltan, Schwab Constantin, Hausser Ingrid, Weis Joachim, Dihlmann Susanne, Böckler Dittmar, Bendszus Martin, Heiland Sabine, Herzig Stephan, Nawroth Peter P, Szendroedi Julia, Fleming Thomas

机构信息

Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.

Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.

出版信息

Diabetes. 2025 Jan 1;74(1):65-74. doi: 10.2337/db24-0493.

DOI:10.2337/db24-0493

PMID:39418320

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11664024/

Abstract

Lesioned fascicles (LFs) 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). Although non-LFs from T2D donors showed activation of neuroprotective pathways, LFs 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 interorgan communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.

摘要

糖尿病性神经病变（DN）患者坐骨神经中的损伤束（LFs）与临床症状严重程度相关。本研究旨在表征这些损伤的结构和分子组成，以更好地理解DN的发病机制。使用离体磁共振神经成像、体外成像和蛋白质组学分析对患有和未患有2型糖尿病（T2D）的截肢者的坐骨神经进行了检查。损伤仅在T2D供体中发现，并表现出明显的结构异常，包括轴突变性、脱髓鞘和血神经屏障（BNB）受损。尽管来自T2D供体的非LFs显示神经保护途径的激活，但LFs缺乏这种反应，而是通过经典途径显示出补体激活增加。肝脏衍生的急性期蛋白的检测表明，BNB破坏促进了肝脏与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。