Progression of axonal excitability abnormalities with increasing clinical severity of diabetic peripheral neuropathy

•There are progressive changes in axonal excitability in DPN in parameters that reflect the activity of axonal Kv1.1 channels.•Mathematical modelling shows that excitability changes in severe DPN are explained by an increase in Kv1.1 conductances.•Blockade of Kv1.1 channels may be a suitable treatment target for diabetic peripheral neuropathy. Diabetic peripheral neuropathy (DPN) is a frequent complication for persons with type 2 diabetes. Previous studies have failed to demonstrate any significant impact of treatment for DPN. The present study assessed the role of axonal ion channel dysfunction in DPN and explored the hypothesis that there may be a progressive change in ion channel abnormalities that varied with disease stage. Neurophysiological studies were conducted using axonal excitability techniques, a clinical method of assessing ion channel dysfunction. Studies were conducted in 178 persons with type 2 diabetes, with participants allocated into four groups according to clinical severity of neuropathy, assessed using the Total Neuropathy Grade. Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of Kv1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10–20 ms (p