EXPERIMENTAL DIABETIC AUTONOMIC NEUROPATHY

糖尿病自主神经病变是导致糖尿病的重要临床问题。 糖尿病的发病率和死亡率显著增加。在……里面 目的探讨糖尿病自主神经病变的发病机制及临床意义。 它的改进，代表了这个项目的长期目标 调查发现，我们已经开发出一种重复性很高的神经病理学 实验性糖尿病自主神经病变模型。常客 变性、再生和营养不良的无髓鞘轴突的发生 已证实在回肠系膜和远端消化道 慢性链脲佐菌素诱导的糖尿病大鼠。在最近的研究中 已完成的、详细的超微结构表征 轴突损害、发展的时间进程、解剖分布和 神经节后受累的免疫细胞化学证据 交感神经轴突已经完成。我们已经完全成功地 应用胰岛预防神经病的发展 移植或每日胰岛素治疗在几周内开始 糖尿病状态的诱导和我们已经接近完成 胰岛后遗神经病的解决方法 移植。拟议的研究将继续进行详细的 神经病变的超微结构、形态计量学、超微结构特征 生化、免疫细胞化学和生理学方法。几种可能的情况 将研究致病机制以阐明改变的作用。 探讨轴突运输在轴索病变发展中的作用 山梨醇和肌醇代谢在其发病机制中的作用 考察年龄对其发育的影响。这一假设认为 实验性糖尿病自主神经病变的特征性轴突病变 代表受挫的轴突再生将得到最终的检验。我们 将决定实验性糖尿病的生理后果 涉及消化道神经支配的神经病。我们会 确定我们开发的致病机制是否对 糖尿病自主神经病变通过检查丙烯酰胺自主神经病变， 我们发现它有许多结构特征与 实验性糖尿病的无髓鞘轴索病变。

Diabetic autonomic neuropathy is an important clinical problem resulting in a significant increase in the morbidity and mortality of diabetes. In order to investigate the pathogenesis of diabetic autonomic neuropathy and its amelioration, which represent the long term objectives of this investigation, we have developed a highly reproducible neuropathologic model of experimental diabetic autonomic neuropathy. The regular occurrence of degenerating, regenerating, and dystrophic unmyelinated axons has been demonstrated in the ileal mesentery and distal alimentary tract of rats with chronic streptozotocin-induced diabetes. In studies recently completed, detailed characterization of the ultrastructural appearance of axonal lesions, time course of development, anatomic distribution, and immunocytochemical evidence for the involvement of post-ganglionic sympathetic axons has been accomplished. We have succeeded in completely preventing the development of the neuropathy using pancreatic islet transplantation or daily insulin therapy instituted within a few weeks of induction of the diabetic state and we have achieved nearly complete resolution of established neuropathy following pancreatic islet transplantation. The proposed studies will continue the detailed characterization of the neuropathy using ultrastructural, morphometric, biochemical, immunocytochemical and physiologic methods. Several possible pathogenic mechanisms will be examined to clarify the role of alterations of axonal transport in the development of the axonopathy, to investigate the role of sorbitol and myoinositol metabolism in its pathogenesis, and to examine the effect of age on its development. The hypothesis that the distinctive axonal lesions of experimental diabetic autonomic neuropathy represent frustrated axonal regeneration will be tested definitively. We will determine the physiologic consequences of experimental diabetic neuropathy involving the innervation of the alimentary tract. We will determine if the pathogenetic mechanisms we develop are specific for diabetic autonomic neuropathy by examining acrylamide autonomic neuropathy, which we have found has many structural features in common with the unmyelinated axonopathy of experimental diabetes.