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明确。 高血糖 导致人糖尿病性神经病变中的神经缺血。 至关重要 以确定微血管病变是否在 致病作用或变化是否代表晚期或 次要变化。 为了解决这个重要问题，我们研究了慢性 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，在一个阶段之前的florid 导致纤维变性。 有必要证明， 神经内膜缺氧可导致神经纤维变性。 我们取得了 在过去的八年里取得了巨大的进步。 神经内膜的存在 缺氧现在已经得到了很好的证实， 缺氧的结果可能包括前列环素：血栓素 A2和高级糖基化终产物。 我们建议继续我们的 正在进行的关于糖尿病神经病变发病机制的研究，使用STZ EDN。 主要假设是EDN是一种代谢紊乱， 主要由神经微血管承担。 我们计划将我们的微血管 从周围神经轴突到感觉神经和 交感神经元。 我们将进一步评估慢性 神经干和神经节（感觉和交感）高血糖症 血流量和氧分压 我们将评估 氨基胍逆转神经血流异常， 慢性EDN中的氧张力和神经传导，一项研究， 临床意义 我们将评估氧自由基的作用 (OFR)EDN的活性，以及降低OFR的措施的有效性 改善神经电生理和血神经的活动 屏障 我们计划研究外源性胰岛素对氧的影响 周围神经和神经节的氧释放和神经内膜的氧张力 EDN。 我们还应该能够用数学模型来模拟 胰岛素对氧气释放的影响 这些方法中有几种可能是 适用于人类糖尿病神经病变的管理。