Cutaneous Measeures of Diabetic Neuropathy

描述（由申请人提供）：糖尿病神经病变（DN）是残疾的重要原因。糖尿病并发症和控制试验表明，DN在早期治疗时最有效。我们发现神经病变与早期血糖失调有关。与糖尿病和糖耐量受损（IGT）相关的神经病变首先损伤小神经纤维。因此，传统的进展措施，如振动检测阈值和神经传导研究，测量大纤维功能，检测早期DN差。缺乏敏感的措施，小纤维损失限制了研究潜在的治疗时，他们有最大的成功机会。皮肤活检和表皮内神经纤维密度（IENFD）的测量是一个敏感的，定量的和可重复的测量小纤维损伤，但纵向数据相关的IENFD与临床神经病变进展是不可用的。早期微血管损伤在DN的发病机制中起重要作用。高血糖症的代谢后果（多元醇途径的激活、晚期糖基化终产物和活性氧的形成）损害血管扩张剂一氧化氮的释放并引起内皮损伤和神经缺血。激光多普勒是测量皮肤微血管血流变化的敏感手段。DN患者显示乙酰胆碱离子导入后皮肤血管舒张减少，与一氧化氮功能缺陷一致。我们假设：（1）IENFD将是早期DN进展的敏感指标，（2）皮肤激光多普勒血流缺损将与IENFD下降相关（3），并将预测临床定义的DN的发展。我们将建立IENFD对DN进展的敏感性，并将变化与传统终点指标相关联。将对一组无神经病变的糖尿病受试者进行随访，以确定基线IENFD或一年内IENFD的变化率是否可预测未来发生临床神经病变。IENFD将与乙酰胆碱离子导入后使用激光多普勒血流的微血管功能障碍相关。我们将确定微血管变化是否先于小纤维神经损失或预测神经损失。微血管变化和IENFD将与血糖控制相关。这些结果将有助于未来DN治疗试验的设计，并为微血管功能障碍在糖尿病小纤维神经病变发病机制中的作用提供重要信息。

DESCRIPTION (provided by applicant): Diabetic neuropathy (DN) is a significant cause of disability. The Diabetes Complications and Control Trial suggests DN is most responsive when treated early. We find neuropathy is associated with early glucose dysregulation. Neuropathy associated with diabetes and impaired glucose tolerance (IGT) injures small nerve fibers first. Consequently, traditional progression measures such as vibration detection threshold and nerve conduction studies, which measure large fiber function, detect early DN poorly. The lack of sensitive measures of small fiber loss limits study of potential therapies when they have the greatest chance of success. Skin biopsy with measurement of intraepidermal nerve fiber density (IENFD) is a sensitive, quantitative and reproducible measure of small fiber injury, but longitudinal data correlating IENFD with clinical neuropathy progression is not available. Early microvascular injury is important in the pathogenesis of DN. Metabolic consequences of hyperglycemia (activation of the polyol pathway, formation of advanced glycation endproducts and reactive oxygen species) impair release of the vasodilator nitric oxide and cause endothelial injury and nerve ischemia. Laser Doppler is a sensitive means of measuring change in cutaneous microvascular blood flow. Patients with DN display reduced cutaneous vasodilatation after iontophoresis of acetylcholine, consistent with a deficit in nitric oxide function. We hypothesize: (1) IENFD will be a sensitive measure of early DN progression, (2) cutaneous laser Doppler flow deficits will correlate with IENFD decline (3) and will predict development of clinically defined DN. We will establish the sensitivity of IENFD to DN progression and correlate change with traditional endpoint measures. A group of diabetic subjects without neuropathy will be followed in order to determine if baseline IENFD, or rate of change in IENFD over one year, predicts future development of clinical neuropathy. IENFD will be correlated with microvascular dysfunction using laser Doppler flow following iontophoresis of acetylcholine. We will determine if microvascular changes precede small fiber nerve loss or predict nerve loss over time. Microvascular changes and IENFD will be correlated with glycemic control. The results will aid in the design of future therapeutic trials in DN and provide important information regarding the role of microvascular dysfunction in the pathogenesis of diabetic small fiber neuropathy.