DIABETIC NEUROPATHY

糖尿病神经病变

• 批准号: 3417428
• 负责人: PHILLIP A LOW
• 金额: $ 22.47万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3417428
• 关键词: adenosine triphosphate; allopurinol; aminoguanidine; axon; blood flow measurement; blood glucose; diabetic neuropathy; dipyridamole; dorsal root; electrophysiology; free radical oxygen; ganglions; hyperglycemia; insulin; laboratory rat; mathematical model; metabolism disorder; neural transmission; neurons; neurophysiology; neuroprotectants; oxygen consumption; oxygen tension; pathologic process; peripheral nervous system; respiratory gas; sciatic nerve; streptozotocin; tocopherols

The pathogenesis of diabetic neuropathy is uncertain. Hyperglycemia results in nerve ischemia in human diabetic neuropathy. It was critical to determine whether microvascular pathology plays a central pathogenetic role or whether the changes represent late stage or secondary changes. To approach this important issue we studied chronic streptozotocin (STZ) experimental diabetic neuropathy (EDN) seeking evidence of endoneurial hypoxia, and ischemia, at a stage before florid fiber degeneration resulted. It was necessary to demonstrate that endoneurial hypoxia preceeded fiber degeneration. We have made excellent progress in the past 8 years. The presence of endoneurial hypoxia is now well-established and mechanisms by which hyperglycemia results in hypoxia may include alterations in prostacyclin: thromboxane A2 and advanced glycosylation end-products. We propose to continue our ongoing studies on the pathogenesis of diabetic neuropathy, using STZ EDN. The major hypothesis is that EDN is a metabolic disorder, with the brunt borne by nerve microvessels. We plan to extend our microvascular physiologic studies from peripheral nerve axon to sensory and sympathetic neurons. We will further evaluate the role of chronic hyperglycemia on nerve trunk and ganglionic (sensory and sympathetic) blood flow and oxygen tension. We will evaluate the efficacy of aminoguanidine in reversing the abnormalities of nerve blood flow, oxygen tension and nerve conduction in chronic EDN, a study of great clinical significance. We will evaluate the role of oxygen free radical (OFR) activity in EDN, and the efficacy of measures that reduce OFR activity in improving nerve electrophysiology and the blood-nerve barrier. We plan to study the effect of exogenous insulin on oxygen release and endoneurial O2 tension in peripheral nerve and ganglia of EDN. We should also be able to mathematically model the effect of insulin on oxygen release. Several of these approaches are potentially applicable to the management of human diabetic neuropathy.

糖尿病神经病变的发病机制尚不清楚。 高血糖 导致人类糖尿病神经病变的神经缺血。 这很关键 确定微血管病理学是否起着核心作用 发病作用或变化是否代表晚期或 二次变化。 为了解决这个重要问题，我们研究了慢性病 链脲佐菌素 (STZ) 实验性糖尿病神经病变 (EDN) 寻求 神经内膜缺氧和缺血的证据，在花期之前的阶段 导致纤维变性。 有必要证明 神经内膜缺氧先于纤维变性。 我们已经做了 过去8年取得了巨大进步。 神经内膜的存在 缺氧现在已经很成熟，高血糖的机制 缺氧的结果可能包括前列环素：血栓素的改变 A2 和高级糖基化终产物。 我们建议继续我们的 正在进行的使用 STZ 进行糖尿病神经病变发病机制的研究 电子数据网络。 主要假设是 EDN 是一种代谢紊乱， 首当其冲的是神经微血管。 我们计划扩展我们的微血管 从周围神经轴突到感觉和感觉的生理学研究 交感神经元。 我们将进一步评估慢性病的作用 神经干和神经节（感觉和交感神经）高血糖 血流量和氧张力。 我们将评估其功效 氨基胍逆转神经血流异常， 慢性 EDN 中的氧张力和神经传导，一项重大研究 临床意义。 我们将评估氧自由基的作用 EDN 中的 (OFR) 活动，以及减少 OFR 措施的有效性 改善神经电生理学和血液神经的活性 障碍。 我们计划研究外源性胰岛素对氧气的影响 周围神经和神经节的释放和神经内氧张力 电子数据网络。 我们还应该能够对效果进行数学建模 胰岛素对氧气释放的影响。 其中一些方法有可能 适用于治疗人类糖尿病神经病变。