Nodal persistent Na C currents in human diabetic nerves estimated by the technique of latent addition Sonoko Misawa a, * , Satoshi Kuwabara a , Kazuaki Kanai a , Noriko Tamura a , Miho Nakata a , Kazue Ogawara 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 See Editorial, pages 712–713 Abstract Objective: To investigate the effects of hyperglycemia on persistent Na C currents in human diabetic nerves, eliminating the factors of passive membrane properties as a factor. Previous studies show that strength–duration time constant of a nerve is shortened under hyperglycemia, suggesting reduced axonal persistent Na C currents. However, the time constant is also affected by changes in passive membrane properties. Latent addition using computerized threshold tracking is a new method that can separately evaluate Na C currents and passive membrane properties. Methods: Latent addition was used to estimate nodal Na C currents in median motor axons of 83 diabetic patients. Brief hyperpolarizing conditioning current pulses were delivered, and threshold changes at the conditioning-test interval of 0.2 ms were measured as an indicator of nodal persistent Na C currents. Seventeen patients were examined before and after insulin treatment. Results: There was an inverse linear relationship between hemoglobin A1c levels and threshold changes at 0.2 ms (PZ0.02); the higher hemoglobin A1c levels were associated with smaller threshold changes. After insulin treatment, there was a significant improvement in nerve conduction velocities associated with greater threshold changes at 0.2 ms (PZ0.03), suggesting an increase in persistent Na C currents. The fast component of latent addition, an indicator of passive membrane properties, was not affected by the state of glycemic control. Conclusions: Hyperglycemia could suppress nodal persistent Na C currents, presumably because of reduced trans-axonal Na C gradient or impaired Na C channels, and this can be rapidly restored by glycemic control. Significance: Reduced nodal Na C currents may partly contribute to the pathophysiology of human diabetic neuropathy. q 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetic neuropathy; Na C channel; Persistent Na C current; Latent addition; Strength–duration time constant 1. Introduction It is generally assumed that activation of polyol pathway and a resulting decrease in Na C –K C ATPase activity, play an important role in the development of diabetic neuropathy (Greene et al., 1987; Sima, 1996). Dysfunction of Na C –K C pump would lead to intra-axonal Na C accumulation and thereby, reduced inward nodal Na C currents. In the mammalian myelinated axons, 1.0–2.5% of the total Na C conductance is active at the resting membrane potential, termed as a ‘persistent’ Na C conductance (Bostock and Rothwell, 1997). Previous studies measuring axonal excitability indices showed shortened strength–duration time constant (SDTC) during hyperglycemia, and this could suggest reduced nodal Na C currents in diabetic patients (Kitano et al., 2004; Misawa et al., 2004, 2005); because SDTC partly depends on persistent Na C con- ductance (Baker and Bostock, 1997; Bostock and Rothwell, 1997; Mogyoros et al., 1998). However, SDTC is also affected by passive membrane properties at the nodes of Ranvier (Bostock et al., 1998; Burke et al., 2001), and therefore it has not been established whether the reduced Clinical Neurophysiology 117 (2006) 815–820 www.elsevier.com/locate/clinph 1388-2457/$30.00 q 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.11.019 * Corresponding author. Tel.: C81 43 222 7171x5414; fax: C81 43 226 2160. E-mail address: sonoko.m@mb.infoweb.ne.jp (S. Misawa).