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

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

doi:10.2337/db24-0493

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

Diabetes. 2024 Oct 17:db240493. doi: 10.2337/db24-0493. Online ahead of print.

Authors

Daniel Schwarz¹, Maxime Le Marois², Volker Sturm¹, Andreas S Peters^{3

4}, Rémi Longuespée⁵, Dominic Helm⁶, Martin Schneider⁶, Bastian Eichmüller², Asa S Hidmark², Manuel Fischer¹, Zoltan Kender^{2

7}, Constantin Schwab⁸, Ingrid Hausser⁸, Joachim Weis⁹, Susanna Dihlmann³, Dittmar Böckler³, Martin Bendszus¹, Sabine Heiland¹, Stephan Herzig^{7

10

11

12}, Peter P Nawroth^{2

13}, Julia Szendroedi^{2

7

11}, Thomas Fleming^{2

7

11}

Affiliations

¹ Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
² Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
³ Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.
⁴ Vascular biomaterial bank Heidelberg, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.
⁵ German Cancer Research Center (DKFZ), Heidelberg, Division of Metabolic Crosstalk in Cancer and the German Cancer Consortium (DKTK), DKFZ Core Center Heidelberg, 69120 Heidelberg, Germany.
⁶ Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany.
⁸ Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224 69120 Heidelberg, Germany.
⁹ Institute of Neuropathology, RWTH Aachen, University Hospital, Aachen, Germany.
¹⁰ Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
¹¹ Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany.
¹² Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany.
¹³ Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany.

PMID: 39418320
DOI: 10.2337/db24-0493

Abstract

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.