Diabetic peripheral neuropathy (DPN) is one of diabetes's most devastating complications, causing numbness, pain, and ultimately limb loss in severe cases. Despite affecting millions, the detailed cellular changes in human nerves have remained poorly characterized. A study in the Journal of Clinical Investigation uses transcriptomics on actual human nerves to map what's happening at the molecular level.
Getting the Tissue
Here's something remarkable: the researchers obtained tibial and sural nerves from lower leg amputations in diabetic patients. This gave them access to deeply affected human tissue that's normally impossible to study - nerves that have been damaged by years of metabolic stress.
They compared these to control sural nerves from cross-facial nerve graft surgeries (reconstructive procedures that harvest small nerves for grafts).
Inflammation and Sensory Changes
Comparing DPN nerves to controls revealed two major themes: inflammatory activation and sensory changes. The nerves were essentially inflamed and showed altered sensory neuron gene expression.
Spatial transcriptomics - which maps gene expression to specific tissue locations - revealed that immune cell populations shifted as axonal loss progressed. The inflammatory profile wasn't static but evolved with disease severity.
mRNAs Travel Down Axons
One intriguing finding: the researchers saw changes in neuronal transcripts like PRPH in nerves with axonal loss, suggesting problems with RNA transport into distal axons.
This led them to investigate whether mRNAs are normally transported down human sensory axons - and they found robust localization of transcripts including SCN9A (a sodium channel) and TRPV1 (a heat and pain receptor). Disruption of this axonal mRNA transport could contribute to nerve degeneration.
Clinical Implications
Understanding the cellular and molecular changes in DPN could eventually guide treatment development. The finding that inflammation evolves with disease progression suggests potential windows for intervention. And the mRNA transport angle offers a novel mechanism that might be therapeutically targetable.
Reference: Tavares-Ferreira D, et al. (2025). Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy. Journal of Clinical Investigation. doi: 10.1172/JCI184075 | PMID: 40828619
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.