Introduction: Based on quantitative sensory testing (QST) we described the progression of diabetic sensorimotor polyneuropathy (DSPN) from healthy to thermal hyperalgesia, to mechanical hyperalgesia, to sensory loss. While QST provides valuable insights, it gives less information about the level of sensory impairment (transductional vs axonal). Therefore, we performed an electrical stimulation protocol to evaluate C-nociceptor excitability in individuals with DSPN. Methods: We examined 66 individuals with diabetes mellitus, 51 having varying stages of DSPN. Slow depolarizing transcutaneous currents of low-intensity with 4 Hz sinusoidal stimulation profile and single 500 ms half sine wave pulses were used to stimulate C-fibers. Pain perception was quantified using (0-10)-Numeric-Rating-Scale. Findings were cross-referenced with QST Z-scores and correlated to serum levels of the axonal marker neurofilament light chain (NfL). Results: Mechanical pain scores positively correlated with electrically induced pain (r=0.757, P<0.001) whereas only a weak positive correlation was found between electrical pain and thermal pain Z-scores at high stimulation intensities (r=0.403, P<0.01). Increased electrical pain ratings were found in individuals with reduced heat pain but not in participants with reduced mechanical pain indicating a possible axonal degeneration in the latter. In most of our subjective sensory tests, higher NfL levels correlated with impaired sensory function (r>-0.3, P<0.05). Conclusion: Loss of mechanical pain indicated axonal degeneration, while absent heat sensation with normal electrically induced pain suggested a progression involving impaired transduction or superficial degeneration of sensory endings. Hypersensitivity to weak depolarizing stimuli may offer insights into DSPN's natural course, aiding high-risk patient identification and guiding interventions. Disclosure O. Eldesouky: None. L. Seebauer: Other Relationship; Springer Medizin Verlag GmbH. R. Rukwied: None. R. Carr: None. M. Roshan: None. A. Sulaj: None. D. Tsilingiris: None. S. Kopf: Speaker's Bureau; Lilly Diabetes, Bayer Inc. T.H. Fleming: None. M. Schmelz: Consultant; Lilly GmbH, Merz Therapeutics, Bayer Inc., Medtronic GmbH. J. Szendroedi: None. Z. Kender: None.