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

OBJECTIVE

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.

METHODS

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.

RESULTS

Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of K1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10-20 ms (p < 0.001), and mathematical modelling of axonal excitability findings supported progressive upregulation of K1.1 conductances with increasing greater disease severity.

CONCLUSION

The findings are consistent with a progressive upregulation of juxtaparanodal K1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy.

SIGNIFICANCE

From a translational perspective, the study suggests that blockade of K1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN.