PATHOLOGIC ABNORMALITIES OF SURAL NERVES IN DIABETIC NEUROPATHIES

糖尿病神经病腓肠神经病理异常

• 批准号: 3846552
• 负责人: PETER JAMES DYCK
• 金额: --
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3846552
• 关键词: aminoguanidine; basement membrane; biopsy; blood vessels; carbohydrate metabolism; diabetes mellitus; diabetes mellitus therapy; diabetic neuropathy; disease /disorder model; disease /disorder proneness /risk; electron microscopy; histology; human subject; human tissue; hyperglycemia; hypoglycemia; hypoxia; inflammation; ischemia; laboratory rat; macrophage; mathematical model; myelinopathy; neurotoxins; pathologic process; peripheral blood vessel disorder; peripheral nervous system; peripheral nervous system disorders; vascular endothelium; vascular endothelium permeability

In studies completed in the last 5-year grant period, we found considerable evidence that hypoxic-ischemic injury may be involved in the pathogenesis of diabetic polyneuropathy. Endoneurial microvessel alterations also were found. Endoneurial myoinositol level was not significantly decreased in conventionally treated diabetics, but fructose and sorbitol levels were, and the latter was linearly associated with severity of neuropathy. In the next 5 years we will: 1) continue to study human sural nerves, recruiting more diabetics without and with mild and severe neuropathy and more controls 40 to 65 yr old; 2) study ganglia and segmental nerves of patients with diabetic truncal radiculopathy; and 3) study the neuropathologic, morphometric, and teased-fiber abnormalities and microvascular reactions from hyperglycemia, hypoglycemia, chronic hypoxia, repeated fiber degeneration, and permanent nerve transection. In (3) studies we seek to recognize stereotypic reactions to injury, specific reactions we can then look for in nerves of diabetics. The possible toxic effect of aminoguanidine will also be studied. Determination of the Index of Pathology (Ip) of sural nerves in controls will allow us to develop age- specific normal values. Comparing Ip in diabetics to Ip in controls will allow us to develop minimal neuropathologic criteria for diabetic polyneuropathy and to judge if diabetics have neuropathy and the severity of their neuropathy. The quantitated neuropathologic abnormalities will be compared to minimal clinical (Project 36), risk factors (Project 36), metabolites (Project 37), microvessel alteration (Project 37), and functional alterations (Projects 31 and 38). The microvessel alterations will be tested against neuropathologic alterations and will be used to model whether microhypoxia-ischemia has occurred. One manifestation of human diabetic neuropathy, sudomotor abnormality, has been reproduced in streptozocin diabetes. This can be prevented and ameliorated by strict control of glycemia. We now test whether it is also ameliorated by aldose reductase inhibitors (ARI) or gangliosides. The ultrastructure of nerve terminals to sweat glands in controls and diabetics will be studied. Major advances are expected because the studies are already in progress, other investigators are involved, and tissue is already available.

在过去五年的研究中，我们发现， 缺氧缺血性损伤可能参与发病机制的证据 糖尿病性多发性神经病 同时， found. 神经内膜肌醇水平没有显著降低， 常规治疗的糖尿病患者，但果糖和山梨糖醇水平， 而后者与神经病变的严重程度呈线性相关。 在未来的5年里，我们将：1）继续研究人类腓肠神经， 招募更多的无轻度和重度神经病变的糖尿病患者， 更多的40 - 65岁的对照; 2）研究神经节和节段神经， 糖尿病性神经根病患者; 3）研究 神经病理学、形态学和撕裂纤维异常， 高血糖、低血糖、慢性缺氧、 反复的纤维变性和永久性神经切断 （3） 我们寻求认识到对伤害的刻板反应的研究， 我们可以在糖尿病患者的神经中寻找反应。 可能的有毒物质 还将研究氨基胍的作用。 指数的确定 对照组中腓肠神经的病理学（Ip）将允许我们发展年龄- 具体的正常值。 将糖尿病患者的IP与对照组的IP进行比较， 使我们能够制定糖尿病患者的最低神经病理学标准， 判断糖尿病患者是否有神经病变及其严重程度 他们的神经病变。 定量的神经病理学异常将是 与最低临床（项目36）、风险因素（项目36） 代谢物（项目37），微血管改变（项目37），和 功能改建（项目31和38）。 微血管改变 将针对神经病理学改变进行测试，并将用于 模拟是否发生微缺氧缺血。 的一种表现 人类糖尿病神经病变，泌汗异常，已经在 链脲佐菌素糖尿病。 这是可以预防和改善的严格 控制权。 我们现在测试它是否也改善了醛糖 还原酶抑制剂（ARI）或神经节苷脂。 神经超微结构 将研究对照组和糖尿病患者的汗腺末端。 主要 预期会有进展，因为研究已经在进行中，其他 研究人员已经介入，组织已经可用。