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; Susanne 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

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
, Susanne Dihlmann
, Dittmar Böckler
, Martin Bendszus
, Sabine Heiland
, Stephan Herzig
, Peter P. Nawroth

Julia Szendroedi, Thomas Fleming

Life Sciences

University Hospital Heidelberg
German Cancer Research Center
Helmholtz Zentrum München German Research Center for Environmental Health
University Hospital

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Pages (from-to)	65-74
Number of pages	10
Journal	Diabetes
Volume	74
Issue number	1
DOIs	https://doi.org/10.2337/db24-0493
State	Published - Jan 2025

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SDG 3 Good Health and Well-being

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10.2337/db24-0493

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Schwarz, D., Le Marois, M., Sturm, V., Peters, A. S., Longuespée, R., Helm, D., Schneider, M., Eichmüller, B., Hidmark, A. S., Fischer, M., Kender, Z., Schwab, C., Hausser, I., Weis, J., Dihlmann, S., Böckler, D., Bendszus, M., Heiland, S., Herzig, S., ... Fleming, T. (2025). Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets. Diabetes, 74(1), 65-74. https://doi.org/10.2337/db24-0493

@article{d82f2872818e46e49eb3bb0b345b33b4,

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

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.",

author = "Daniel Schwarz and \{Le Marois\}, Maxime and Volker Sturm and Peters, \{Andreas S.\} and R{\'e}mi Longuesp{\'e}e and Dominic Helm and Martin Schneider and Bastian Eichm{\"u}ller and Hidmark, \{Asa S.\} and Manuel Fischer and Zoltan Kender and Constantin Schwab and Ingrid Hausser and Joachim Weis and Susanne Dihlmann and Dittmar B{\"o}ckler and Martin Bendszus and Sabine Heiland and Stephan Herzig and Nawroth, \{Peter P.\} and Julia Szendroedi and Thomas Fleming",

note = "Publisher Copyright: {\textcopyright} 2024 by the American Diabetes Association.",

year = "2025",

month = jan,

doi = "10.2337/db24-0493",

language = "English",

volume = "74",

pages = "65--74",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "1",

}

Schwarz, D, Le Marois, M, Sturm, V, Peters, AS, Longuespée, R, Helm, D, Schneider, M, Eichmüller, B, Hidmark, AS, Fischer, M, Kender, Z, Schwab, C, Hausser, I, Weis, J, Dihlmann, S, Böckler, D, Bendszus, M, Heiland, S, Herzig, S, Nawroth, PP, Szendroedi, J & Fleming, T 2025, 'Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets', Diabetes, vol. 74, no. 1, pp. 65-74. https://doi.org/10.2337/db24-0493

TY - JOUR

T1 - Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy

T2 - Unveiling Pathogenic Pathways and Targets

AU - Schwarz, Daniel

AU - Le Marois, Maxime

AU - Sturm, Volker

AU - Peters, Andreas S.

AU - Longuespée, Rémi

AU - Helm, Dominic

AU - Schneider, Martin

AU - Eichmüller, Bastian

AU - Hidmark, Asa S.

AU - Fischer, Manuel

AU - Kender, Zoltan

AU - Schwab, Constantin

AU - Hausser, Ingrid

AU - Weis, Joachim

AU - Dihlmann, Susanne

AU - Böckler, Dittmar

AU - Bendszus, Martin

AU - Heiland, Sabine

AU - Herzig, Stephan

AU - Nawroth, Peter P.

AU - Szendroedi, Julia

AU - Fleming, Thomas

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85213596911

U2 - 10.2337/db24-0493

DO - 10.2337/db24-0493

M3 - Article

C2 - 39418320

AN - SCOPUS:85213596911

SN - 0012-1797

VL - 74

SP - 65

EP - 74

JO - Diabetes

JF - Diabetes

IS - 1

ER -

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

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