Electrophysiologic Measurements in Diabetic Neuropathy

描述（由申请人提供）：糖尿病自主神经病变（DAN）是一种复杂、破坏性和研究不足的疾病，影响数百万患者的生活质量、发病率和死亡率。自主神经的临床表现、组织病理学和可能的电生理学变化可以单独发生，也可以与躯体糖尿病神经病变无关。目前通过评估受自主神经支配的器官的行为来估计DAN的做法是有问题的，因为除了神经病变之外，这些系统还受到多种因素的深刻影响。这个建议的中心论点是，它是可行的，非常可取的，以开发一个电池的电生理措施，能够检查多个方面的自主神经的神经活动，包括传导速度，反应幅度，不应期和神经疲劳。我们建议调整电生理方法，已成功地记录中枢神经系统的活动，以测量缓慢，非同步信号的自主神经和网络的主要无髓鞘轴突，形成自主神经丛和神经节。这些新技术将应用于STZ诱导的高血糖大鼠和Zucker糖尿病脂肪（ZDF）大鼠，分别作为1型和2型糖尿病模型。在早期和晚期时间点，电生理结果将与DAN的组织病理学和形态测量相关。这些平行研究将深入了解与高血糖相关的自主神经功能和结构缺陷的发生和进展，并将大大提高我们区分有效治疗的能力，特别是当它们影响自主神经系统时。概述的研究是连续的。首先，我们将评估技术创新（例如，新电极，非线性分析）来定义正常大鼠中有用的一组测量;然后判断最佳的方法将是糖尿病模型，并最终用于评估两种假定的治疗干预（即，ARI和脂溶性硫胺素衍生物）。如果成功，这些研究将导致新的方法，更敏感的动物模型和更好地了解DAN功能缺陷的性质，幅度，时间过程和治疗反应。

DESCRIPTION (provided by applicant): Diabetic autonomic neuropathy (DAN) is a complex, devastating and understudied condition, affecting the quality of life, morbidity and mortality of millions of patients. Clinical presentation, histopathology and presumably electrophysiologic changes in autonomic nerves can occur in isolation or be dissociated from somatic diabetic neuropathy. The current practice of estimating DAN by evaluating the behavior of organs innervated by autonomic nerves is problematic, since these systems are profoundly influenced by multiple factors in addition to neuropathy. The central thesis of this proposal is that it is both feasible and highly desirable to develop a battery of electrophysiologic measures capable of examining multiple facets of neural activity in autonomic nerves, including conduction velocity, response amplitudes, refractory periods and neural fatigue. We propose to adapt electrophysiologic methods that have been successful in recording of CNS activity to measure the slow, non-synchronous signals in autonomic nerves and in the network of largely unmyelinated axons that form autonomic plexuses and ganglia. These novel techniques will be applied to rats with STZ-induced hyperglycemia and Zucker Diabetic Fatty (ZDF) rats, as models of type 1 and type 2 diabetes, respectively. At both early and late time points, the electrophysiologic findings will be correlated with histopathology and morphometric measures of DAN. These parallel studies will provide insight into the onset and progression of functional and structural deficits in autonomic nerves associated with hyperglycemia and will substantially improve our ability to differentiate effective therapies, especially as they impact the autonomic system. The outlined studies are sequential. First we will evaluate technical innovations (eg., novel electrodes, non-linear analyses) to define a useful battery of measures in normal rats; the methods judged optimal will then be diabetic models, and finally used to evaluate the effects of two putative therapeutic interventions (ie., an ARI and lipid soluble thiamine derivative). If successful, these studies will result in new methods, more sensitive animal models and a better understanding of the nature, magnitude, time course, and response to therapy of functional deficits in DAN.