Cutaneous Measeures of Diabetic Neuropathy

糖尿病神经病变的皮肤测量

• 批准号: 6882081
• 负责人: A. Gordon Smith
• 金额: $ 44.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882081
• 关键词: axon; biomarker; biopsy; clinical research; diabetic neuropathy; diagnosis design /evaluation; early diagnosis; human subject; longitudinal human study; medical complication; nerve injury; nitric oxide; noninsulin dependent diabetes mellitus; outcomes research; pathologic process; ultrasound blood flow measurement; vasodilation

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.

描述（由申请人提供）：糖尿病神经病（DN）是造成残疾的重要原因。糖尿病并发症和控制试验表明，早期治疗时DN的反应最高。我们发现神经病与早期葡萄糖失调有关。与糖尿病和葡萄糖耐受性受损（IGT）有关的神经病首先会损害小神经纤维。因此，传统的进展措施，例如振动检测阈值和神经传导研究，这些研究测量了较大的纤维功能，较早的DN检测不良。缺乏对潜在疗法的小纤维损失限制限制的敏感度量，当它们取得了最大的成功机会。皮肤活检通过测量表皮内神经纤维密度（IENFD）是对小纤维损伤的敏感，定量和可重复的量度，但纵向数据与IENFD与临床神经病进展相关。早期微血管损伤在DN的发病机理中很重要。高血糖途径的代谢后果（聚元途径的激活，高级糖基化终产物的形成和活性氧）会损害血管舒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敏感手段。 DN患者在乙酰胆碱离子噬菌体后的皮肤血管舒张降低，与一氧化氮功能的缺陷一致。我们假设：（1）IENFD将是对早期DN进展的敏感度量，（2）皮肤激光多普勒流量缺陷将与IENFD下降（3）相关，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，并将变化与传统端点度量相关联。将遵循一组没有神经病的糖尿病患者，以确定基线IENFD或一年内IENFD的变化率是否可以预测临床神经病的未来发展。 IENFD将与乙酰胆碱离子噬菌体后的激光多普勒流相关，与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丧失或预测神经丧失。微血管变化和IENFD将与血糖控制相关。结果将有助于设计DN的未来治疗试验，并提供有关微血管功能障碍在糖尿病小纤维神经病发病机理中的作用的重要信息。