Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease using transcriptomics on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population and control sural nerves from cross-facial nerve graft surgery. First, comparing DPN versus control sural nerves revealed inflammatory activation and sensory changes in DPN. Second, when comparing mixed sensory and motor tibial and purely sensory sural nerves, we identified key pathway differences in affected DPN nerves, with distinct immunological features observed in sural nerves. Third, spatial transcriptomics of sural nerves revealed shifts in immune cell types associated with axonal loss progression. We also found clear evidence of neuronal transcript changes, like PRPH, in nerves with axonal loss, suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons, generating evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work provides insight into altered cellular and transcriptomic profiles in human nerves in DPN and highlights sensory axon mRNA transport as a potential contributor to nerve degeneration.