Hyperglycemia alters refractory periods in human diabetic neuropathy Sonoko Misawa a, * , Satoshi Kuwabara a , Kazue Ogawara a , Yukiko Kitano a , Kazuo Yagui b , Takamichi Hattori a a Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan b The Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Accepted 8 June 2004 Available online 10 July 2004 Abstract 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 þ –K þ ATPase activity, probably resulting in a decrease in the trans-axonal Na þ gradient and reduced nodal Na þ 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 ðP ¼ 0:02Þ: Diabetic patients with good glycemic control (HbA1c levels , 7%) had longer RPs than patients with poorer glycemic control and normal controls ðP ¼ 0:01Þ: 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 þ currents, and thereby to a lower inactivation of Na þ channels when generating an action potential. Significance: RP measurements could provide new insights into the ionic pathophysiology of human diabetic neuropathy. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetic neuropathy; Refractory period; Refractoriness; Sodium channel 1. Introduction Diabetic polyneuropathy results from a complex inter- play between metabolic factors directly related to hyper- glycemia (Sima and Brismar, 1985; Sima et al., 1986, 1988; Greene et al., 1999) and structural changes such as axonal degeneration and demyelination caused by microangiopathy (Yasuda and Dyck, 1987; Dyck et al., 1986; Dyck and Giannini, 1996). The major metabolic hypotheses include activation of the polyol pathway and decreased Na þ –K þ ATPase activity. The conversion of excess glucose to sorbitol, and the resulting depletion of myo-inositol that leads to inactivation of Na þ –K þ ATPase activity, are postulated to play an important role in the pathophysiology of diabetic neuropathy (Sima and Brismar, 1985; Sima et al., 1986). Both the high intra-axonal sorbitol concentration and decreased Na þ –K þ pump function would cause intra-axonal Na þ accumulation, resulting in a decrease in the Na þ gradient across the axolemma. In experimental diabetic animals, reduced nodal Na þ currents, when generating an action potential, have been reported (Brismar et al., 1987; Brismar, 1993; Quasthoff, 1998). The refractory period has been shown to be a useful measure of subtle nerve dysfunction (Shefner and Dawson, 1990). Previous studies showed that refractory periods were prolonged in patients with peripheral neuropathy (Shefner and Dawson, 1990; Braume, 1999), but the results of refractory period measurement in diabetic neuropathy have been some- what conflicting; a recent report showed that the absolute refractory periods of single sensory axons were significantly shorter, rather than longer as expected, for diabetic patients than for normal subjects (Mackel and Brink, 2003). The refractory period primarily depends on the inacti- vation of Na þ channels caused by prior depolarization (Bostock et al., 1998; Burke et al., 2001). Considering 1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.06.008 Clinical Neurophysiology 115 (2004) 2525–2529 www.elsevier.com/locate/clinph * Corresponding author. Tel.: þ81-43-222-7171x5414; fax: þ 81-43- 226-2160. E-mail address: sonoko.m@mb.infoweb.ne.jp (S. Misawa).