Insights into inflammation and axonal loss in human diabetic neuropathy: a real step forward

Aims: Tavares et al aimed to identify the key cellular and molecular mechanisms underlying nerve degeneration in human diabetic peripheral neuropathy (DPN).

Methods: To that end, they analyzed human tibial and sural nerves from lower-limb amputations of mostly diabetic patients, alongside control sural nerves from nerve graft surgeries. Bulk RNA-seq, Visium spatial transcriptomics, Xenium imaging, RNAscope in situ hybridization, and proteomics were applied to map gene expression, cell-type composition, intercellular signaling pathways, and axonal mRNA transport patterns.

Results: The study showed that DPN sural nerves display a strong inflammatory profile, with over 2,000 genes altered and marked increases in cytokine and neuropeptide expression alongside reductions in sensory and neurodevelopmental pathways. Spatial transcriptomics revealed a clear progression from early perineurial barrier disruption to rising immune and endothelial cell infiltration, followed by Schwann cell loss and fibrotic expansion in severe axonal degeneration. Comparisons between sural and tibial nerves highlighted stronger inflammatory and vascular changes in sensory nerves, while tibial nerves showed more axonal biology–related alterations. As axonal loss advanced, signaling networks shifted from regenerative pathways in moderate disease to fibrotic, pro-inflammatory pathways in severe cases. Finally, the authors confirmed that key neuronal mRNAs such as SCN9A and TRPV1 localize within human sensory axons, supported by RNA-binding proteins, suggesting that impaired axonal mRNA transport may contribute to nerve degeneration in DPN.

Conclusions: Human DPN nerves exhibit a coordinated inflammatory, vascular, and fibrotic remodeling process accompanied by Schwann cell depletion and altered axonal mRNA distribution. The data reveal distinct cellular dynamics in sensory vs mixed nerves and highlight RNA transport and local translation as potential contributors to axonal vulnerability in DPN.

Comments: This study offers a rare and compelling look into human peripheral nerves affected by diabetes, revealing a dynamic shift toward inflammation, vascular remodeling, and Schwann cell loss as neuropathy advances. By integrating multiple high-resolution techniques, the authors deliver one of the most detailed molecular maps of DPN to date, highlighting not only the rising inflammatory burden but also the intriguing role of axonal mRNA transport in maintaining nerve integrity. The discovery of sensory axon–localized transcripts such as SCN9A and TRPV1 adds a fresh mechanistic angle with real therapeutic potential. Although human nerve samples are inherently limited and often represent advanced disease, the depth and coherence of these findings make this work an important step forward. Overall, the study broadens our understanding of why nerves fail in diabetes and opens the door to innovative strategies that target both the inflammatory environment and the intrinsic resilience of sensory axons.

Stéphanie Eid

Reference. Tavares-Ferreira D, Shen BQ, Mwirigi JM, Shiers S, Sankaranarayanan I, Sreerangapuri A, Kotamarti MB, Inturi NN, Mazhar K, Ubogu EE, Thomas GL, Lalli T, Rozen SM, Wukich DK, Price TJ. Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy. J Clin Invest. 2025 Aug 19;135(20):e184075. doi: 10.1172/JCI184075. PMID: 40828619; PMCID: PMC12520680.

🔗 https://www.jci.org/articles/view/184075