Structural and molecular signatures of diabetic sciatic nerve lesions from fascicle lesions to liver–nerve crosstalk

Aims: This study aimed to advance understanding of DPN pathogenesis by exploring structural and molecular features of sciatic nerve fascicle lesions in individuals with type 2 diabetes (T2D).

Methods: Sciatic nerve samples from 11 T2D amputees and 4 control samples without T2D were examined using a multimodal design: 1) ex vivo magnetic resonance neurography (MRN) to localize lesions, 2) microscopy to assess micro-and ultrastructural changes, and 3) proteomic profiling of lesioned and non-lesioned nerve segments to identify molecular differences.

Results: Lesioned fascicles were detected exclusively in nerves from individuals with T2D. Structural abnormalities included axonal degeneration, demyelination, and disruption of the blood–nerve barrier (BNB). Proteomic analysis revealed loss of neuroprotective signalling and augmentation of proinflammatory pathways, with upregulation of the classical complement cascade. Interestingly, liver-derived acute phase proteins were identified in lesioned fascicles, suggesting that BNB disruption may permit systemic entry of hepatogenic factors and pointing to a potential liver-nerve pathogenic axis.

Conclusions: Sciatic nerve lesions in T2D display distinct structural and inflammatory hallmarks such as BNB compromise, complement activation, and infiltration of liver-derived proteins. These findings highlight a possible interorgan mechanisms linking hepatic pathology and peripheral nerve damage, offering new perspectives on DPN pathogenesis.

Comments. This study stands out for its integrative design combining ex vivo MRN, ultrastructural imaging, and proteomics within the same nerve samples, offering a uniquely detailed characterization of focal nerve pathology. Importantly, this approach bridges MRN-detectable lesions, previously shown to correlate with DPN severity (Vaeggemose M et al Diabetes. 2017;66:1779-1788), with corresponding morphological and molecular signatures. The identification of lesion-specific complement activation together with infiltration by liver-derived proteins introduces an intriguing and novel systemic dimension to DPN pathogenesis, suggesting that interorgan crosstalk may drive neuropathic changes beyond local nerve pathology. These findings open new therapeutic perspectives, including the potential benefit of improving liver function to slow DPN progression and exploring anticomplement therapies that have already shown promise in autoimmune and degenerative neurological disorders (Dalakas MC et al Nat Rev Neurol. 2020;16:601-617). Limitations include the small sample size and possible confounding due to the ischemic and/or infectious causes of amputation, which could influence proteomic findings. Nevertheless, this study provides a compelling and innovative perspective, proposing interorgan mechanisms in DPN and highlighting avenues for future mechanistic and therapeutic research.

Anders Stouge

Reference. 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. Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets. Diabetes. 2025 Jan 1;74(1):65-74. doi: 10.2337/db24-0493. PMID: 39418320; PMCID: PMC11664024.

🔗 https://diabetesjournals.org/diabetes/article/74/1/65/157392/Exploring-Structural-and-Molecular-Features-of