Hyperglycemia alters refractory periods in human diabetic neuropathy

Objective: To investigate the effects of hyperglycemia on axonal excitability in human diabetics. Diabetic nerve dysfunction is partly associated with the altered polyol pathway and Na+–K+ ATPase activity, probably resulting in a decrease in the trans-axonal Na+ gradient and reduced nodal Na+ currents. Methods: Threshold tracking was used to measure the relative refractory periods (RPs) of median motor axons in 58 diabetic patients, 45 normal subjects, and 12 patients with non-diabetic axonal neuropathy. In diabetic patients, the relationship of RPs with hemoglobin A1c (HbA1c) levels was analyzed. Results: The mean RP was similar for diabetics and normal controls as a group, but was longer in patients with non-diabetic neuropathy than in normal controls (P=0.02). Diabetic patients with good glycemic control (HbA1c levels <7%) had longer RPs than patients with poorer glycemic control and normal controls (P=0.01). RP was longest at the HbA1c level of 6%, gradually decreasing and reaching a plateau at the HbA1c level of 8–9%. Conclusions: Hyperglycemia shortens RPs, possibly because metabolic abnormalities lead to reduced nodal Na+ currents, and thereby to a lower inactivation of Na+ channels when generating an action potential. Significance: RP measurements could provide new insights into the ionic pathophysiology of human diabetic neuropathy.