The acute effects of glycemic control on axonal excitability in human diabetics

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Abstract
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. Ann Neurol 2004;56:462–467