Single myelinated nerve fibres were isolated from the sciatic nerves of the spontaneously diabetic BB-Wistar rat after 17-185 days of overt diabetes. Pronounced demyelination and paranodal changes were found in one rat (diabetes duration 185 days), the others had no structural changes that could be detected light-microscopically. Potential clamp analysis of these fibres showed a decreased Na equilibrium potential (UNa), decreased Na currents caused by large inactivation, and a specific increase in the K-permeability. Measurements with high-K solution outside the node revealed that the decreased UNa was caused by high axoplasmic [Na]. Fibres with increased K-permeability had, in addition, increased nodal leak conductance. Decreased excitability was found in the majority of the fibres and was related to the permeability changes. The present findings indicate that axonal dysfunction (Na-accumulation and inactivation of the Na-permeability) precede the changes (increased K-permeability) related to paranodal demyelination.