Cutaneous Measeures of Diabetic Neuropathy

描述(申请人提供)：糖尿病神经病变(DN)是导致残疾的重要原因。糖尿病并发症和控制试验表明，早期治疗对糖尿病肾病的反应最好。我们发现神经病与早期的葡萄糖调节失调有关。与糖尿病和糖耐量受损(IGT)相关的神经病变首先损害小神经纤维。因此，测量大纤维功能的传统进展指标，如振动检测阈值和神经传导研究，对早期糖尿病肾病的诊断能力较差。缺乏对小纤维损失的敏感测量限制了对潜在疗法的研究，因为这些疗法最有可能成功。皮肤活检和测量表皮内神经纤维密度(IENFD)是一种敏感、定量和重复性好的小纤维损伤指标，但IENFD与临床神经病进展相关的纵向数据尚不可用。早期微血管损伤在糖尿病肾病的发病机制中起重要作用。高血糖的代谢后果(激活多元醇途径，形成晚期糖基化终末产物和活性氧物种)会损害血管扩张剂一氧化氮的释放，并导致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灵敏手段。糖尿病肾病患者在乙酰胆碱离子导入后皮肤血管扩张减少，这与一氧化氮功能缺陷相一致。我们假设：(1)IENFD将是早期糖尿病肾病进展的敏感指标，(2)皮肤激光多普勒血流缺陷将与IENFD下降相关(3)并将预测临床定义的糖尿病肾病和其他微血管并发症的发展。我们将建立IENFD对糖尿病肾病进展的敏感性，并将变化与传统的终点测量相关联。对一组没有神经病变的糖尿病受试者进行跟踪调查，以确定基线IENFD或IENF一年内的变化率是否可以预测临床神经病变的未来发展。应用激光多普勒血流仪对乙酰胆碱离子导入后的微血管功能障碍与IENFD相关。我们将确定微血管变化是否先于小纤维神经丢失，或者随着时间的推移预测神经丢失。微血管改变和IENFD将与血糖控制相关。这些结果将有助于设计未来的糖尿病肾病治疗试验，并提供有关微血管功能障碍在糖尿病小纤维神经病变发病机制中的重要信息。

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 end products 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 and other microvascular complications. 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 IENF 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.