In diabetic nerves, the activation of the polyol pathway and a resulting decrease in Na(+)-K(+) ATPase activity lead to intra-axonal Na(+) accumulation and a smaller Na(+) gradient across the axolemma than normal. To investigate whether glycemic control is associated with acutely reversible changes in axonal excitability and Na(+) conductance, we measured the multiple excitability indices (strength-duration time constant, rheobase, refractoriness, and refractory period) of the median motor axons of 21 diabetic patients before and after intensive insulin treatment. Within 4 weeks after treatment was begun, there was a significant improvement in nerve conduction velocities, associated with increased strength-duration time constant, decreased rheobase, increased refractoriness, and prolonged refractory periods. Assuming that the strength-duration time constant partly reflects persistent Na(+) conductance, and that refractoriness/refractory periods depend on inactivation of transient Na(+) channels caused by prior depolarization (the influx of Na(+)), the patterns of changes in these indices may reflect a reduced trans-axonal Na(+) gradient during hyperglycemia and its restoration by glycemic control in diabetic patients. Measurement of the excitability indices could provide new insights into the pathophysiology of human diabetic neuropathy.