Mismatch between intact electrical excitability and lost heat pain in diabetic neuropathy

Patterns of sensory involvement in diabetic neuropathy vary between studies and diagnostic approaches. Although some report early thermal deficits, others find predominant large-fiber changes, and hypersensitivity in early disease is inconsistently observed. Elevated heat pain thresholds (HPTs) may indicate either selective loss of heat transduction or advanced peripheral denervation of polymodal nociceptors. We examined whether thermal and mechanical pain functions align with psychophysical axonal excitability by combining German Research Network on Neuropathic Pain-quantitative sensory testing with slow depolarizing transdermal electrical stimulation of polymodal C-fibers in 66 adults with diabetes mellitus. Neuropathy was assessed by Toronto Consensus Criteria, quantitative sensory testing (QST), questionnaires, and serum neurofilament light chain (NfL) as a marker of axonal damage. Mechanical pain sensitivity correlated with electrically evoked pain (r ≈ 0.60-0.62, both P < 0.0001), consistent with parallel changes in mechanical transduction and axonal excitability, whereas HPT did not correlate with electrical pain. Many individuals with elevated HPT still exhibited strong electrically evoked pain responses, suggesting impaired heat transduction despite preserved superficial axonal excitability. Participants with sensory loss in QST showed reduced sensitivity to electrical stimuli and higher detection and pain thresholds, consistent with more advanced afferent dysfunction. NfL levels generally correlated with sensory impairment, although at low electrical intensities, higher NfL values were associated with stronger pain ratings, indicating intensity-dependent links between axonal pathology and nociceptor hyperexcitability. Combining QST with C-fiber-targeted electrical testing refines phenotyping of small-fiber dysfunction in diabetic neuropathy by revealing dissociation between thermal and electrical pain modalities and capturing the heterogeneous course from preserved function to selective thermal hypoalgesia and eventual sensory loss.