Potassium channel dysfunction and distinct sensory axonal profiles in painful type 2 diabetes

Objective: This study aims to characterize sensory axonal changes in patients with non-painful and painful type 2 diabetes mellitus (T2DM) to explore the mechanisms underlying diabetic neuropathic pain in relation to pregabalin treatment. Methods: Clinical evaluations, including nerve conduction studies, nerve excitability testing (NET) and visual analogue scale (VAS), were conducted on 200 T2DM, resulting 131 qualifying for inclusion. Cohort stratification utilized VAS scores: 43 had VAS ≥ 4 (painful), and 88 had VAS < 4 (non-painful). The painful cohort was categorized into low pain (4 ≤ VAS < 7) and high pain (VAS ≥ 7). A subgroup receiving pregabalin (15) was assessed to investigate neurophysiological differences. Results: The painful cohort differed significantly from the non-painful cohort in sensory nerve excitability parameters including stimulus for 50% maximum amplitude, refractoriness, superexcitability, subexcitability, and depolarization thresholds. Higher VAS scores correlated with reduced TEd40(Accom) and TEh(overshoot). Pregabalin-treated patients demonstrated improved stimulus–response slope, S2 accommodation and TEd40(Accom) compared to untreated patients. Conclusions: Our findings suggest that diabetic neuropathic pain may be associated with axonal hyperpolarization and accommodative properties with implications to potassium channel dysfunction. Significance: These findings elucidate mechanisms of diabetic pain pathophysiology, highlighting the clinical significance of sensory NET and the role of potassium channel modulation in T2DM pain management.