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

Diabetes, vol. 74, pp. 65–74

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.

Authors 22

1. Daniel F. Schwarz

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

   1Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

2. Maxime Le Marois

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

   2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

3. Volker Jörg Friedrich Sturm

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

   1Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

4. Andreas Sebastian Peters

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Heidelberg, Germany

   4Vascular Biomaterial Bank Heidelberg, Heidelberg University Hospital, Heidelberg, Germany

   3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

   4Vascular biomaterial bank Heidelberg, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

5. Rémi Longuespée

   German Cancer Research Center · Deutsches Konsortium für Translationale Krebsforschung

   Affiliation as printed

   5German Cancer Research Center (DKFZ) Heidelberg, Division of Metabolic Crosstalk in Cancer and the German Cancer Consortium (DKTK), DKFZ Core Center Heidelberg, Heidelberg, Germany

   5German 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. Dominic Helm

   German Cancer Research Center

   Affiliation as printed

   6Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany

7. Martin A. Schneider

   German Cancer Research Center

   Affiliation as printed

   6Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany

8. Bastian Eichmüller

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

   2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

9. Åsa S. Hidmark

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

   2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

10. Manuel Dominik Fischer

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

    1Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

11. Ζoltan Κender

    Heidelberg University · University Hospital Heidelberg · Helmholtz Munich · German Center for Diabetes Research

    Affiliation as printed

    2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    7German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

    9German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

12. Constantin Schwab

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    8Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    7Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224 69120 Heidelberg, Germany

13. Ingrid Haußer

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    8Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    7Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224 69120 Heidelberg, Germany

14. Joachim Weis Aachen 9Institute of Neuropathology 8Institute of Neuropathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    9Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, University Hospital, Aachen, Germany

    8Institute of Neuropathology, RWTH Aachen, University Hospital, Aachen, Germany

15. Susanne Dihlmann

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Heidelberg, Germany

    3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

16. Dittmar Böckler

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Heidelberg, Germany

    3Department for Vascular Surgery and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

17. Martin Bendszus

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

    1Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

18. Sabine Heiland

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

    1Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

19. Stephan Herzig

    Heidelberg University · University Hospital Heidelberg · Helmholtz Munich · German Center for Diabetes Research · Technical University of Munich

    Affiliation as printed

    10Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany

    11Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    12Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany

    7German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

    11Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    9German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

20. Peter P. Nawroth

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    13Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

21. Julia Szendroedi

    Heidelberg University · University Hospital Heidelberg · Helmholtz Munich · German Center for Diabetes Research

    Affiliation as printed

    11Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    7German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

    11Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

    9German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

22. Thomas Henry Fleming corresponding

    Heidelberg University · University Hospital Heidelberg · Helmholtz Munich · German Center for Diabetes Research

    Affiliation as printed

    11Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    7German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany

    11Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany

    2Department for Endocrinology, Diabetology, Metabolic diseases and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

    9German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany