EXPERIMENTAL DIABETIC AUTONOMIC NEUROPATHY

糖尿病自主神经病变是一个重要的临床问题， 糖尿病的发病率和死亡率显著增加。 在 目的探讨糖尿病自主神经病变的发病机制， 它的改善，这代表了长期目标， 研究，我们已经开发出一种高度可重复的神经病理学 实验性糖尿病自主神经病变模型。 经常 发生变性、再生和营养不良的无髓鞘轴突 已经证实，在回肠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， 完成，详细表征的超微结构外观 轴突病变，发展的时间过程，解剖分布，和 免疫细胞化学证据参与节后 交感神经轴突已经完成。 我们已经完全成功地 利用胰岛预防神经病的发展 移植或几周内开始每日胰岛素治疗 诱导糖尿病状态，我们已经实现了几乎完全 胰岛移植后确定的神经病变消退 移植 拟议的研究将继续详细 使用超微结构，形态测量， 生物化学、免疫细胞化学和生理学方法。 几种可能 致病机制将被检查，以澄清改变的作用， 轴突运输在轴突病的发展，调查 山梨醇和肌醇代谢在其发病机制中的作用， 研究年龄对其发展的影响。 的假设 实验性糖尿病自主神经病变的轴索损害 是否代表轴突再生受阻将被明确测试。 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。 我们将 确定我们开发的致病机制是否针对 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， 实验性糖尿病的无髓鞘轴突病。

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.