The Acute Effects of Glycemic Control on Axonal Excitability in Human Diabetics Yukiko Kitano, MD, 1 Satoshi Kuwabara, MD, 1 Sonoko Misawa, MD, 1 Kazue Ogawara, MD, 1 Kazuaki Kanai, MD, 1 Yuriko Kikkawa, MD, 1 Kazuo Yagui, MD, 2 and Takamichi Hattori, MD 1 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 patho- physiology of human diabetic neuropathy. Ann Neurol 2004;56:462– 467 Diabetic polyneuropathy results from a complex inter- play between metabolic factors directly related to hy- perglycemia and structural changes such as axonal de- generation and demyelination. 1–3 The mechanisms underlying nerve dysfunction are not well understood, but it is generally assumed that the metabolic factors mediate acutely reversible functional impairment. The major metabolic factors include activation of the polyol pathway and decreased Na + -K + ATPase activity. The conversion of excess glucose to sorbitol, and the result- ing depletion of myo-inositol that leads to inactivation of Na + -K + ATPase activity would result in intraaxonal Na + accumulation and lead to a decrease in the Na + gradient across the axolemma. 4–6 An altered membra- nous Na + gradient would affect axonal Na + conduc- tance, which can be restored by glycemic control. 1,5,7 Rigorous insulin replacement can result in rapid rever- sal of the Na + -K + ATPase activity, 1,2 and there is ev- idence that the slowing of nerve conduction is caused, in part, by metabolic abnormalities in human diabet- ics. 8 In the 1990s, the threshold tracking technique was developed to measure several axonal excitability indices such as strength-duration properties, refractoriness, su- pernormality, late subnormality, and threshold electro- tonus, noninvasively in human subjects. 9 –12 These in- dices depend on the biophysical properties of the axonal membrane at the site of stimulation and can provide insights into the Na + and K + channel func- tion. We used this technique to investigate whether glycemic control with intensive insulin treatment is as- sociated with specific changes in axonal ionic conduc- tances. Subjects and Methods Patients Twenty-one patients with diabetes mellitus (11 men and 10 women), who were referred to Chiba University Hospital for control of hyperglycemia, were studied. Two had type 1 di- abetes mellitus, and the remaining 19 had type 2 diabetes. They ranged in age from 22 to 82 years (mean, 56 years), with a disease duration of 1 to 20 years (mean, 9 years). Of the 21 patients, 17 had mild-to-moderate diabetic polyneu- ropathy, and the remaining 4 were asymptomatic. We ex- cluded diabetic patients with renal failure because the serum K + level can significantly alter the membrane potential and excitability indices. 13,14 Measurements of their hemoglobin A1c (HbA1c) and fasting blood glucose levels were taken, and electrophysiologic studies were performed before and 4 weeks after the start of intensive insulin treatment (four times per day, subcutaneous injection). From the 1 Department of Neurology and 2 The Second Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan. Received Mar 8, 2004, and in revised form May 17 and Jun 17. Accepted for publication Jun 18, 2004. Published online Sep 30, 2004, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20232 Address correspondence to Dr Kuwabara, Department of Neurol- ogy, Chiba University School of Medicine 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. E-mail: kuwabara-s@faculty.chiba-u.jp ORIGINAL ARTICLES 462 © 2004 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services