Electrophysiologic Measurements in Diabetic Neuropathy

描述(申请人提供)：糖尿病自主神经病变(DAN)是一种复杂的、破坏性的和未被研究的疾病，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改变可以单独发生，也可以与躯体糖尿病神经病变分离。目前通过评估自主神经支配的器官的行为来评估DAN的做法是有问题的，因为这些系统除了神经病变外，还受到多种因素的深刻影响。这一建议的中心论点是，开发一套能够检测自主神经神经活动的多个方面的电生理指标是可行的，也是非常可取的，包括传导速度、反应幅度、不应期和神经疲劳。我们建议采用已经成功记录CNS活动的电生理学方法来测量自主神经和形成自主神经丛和神经节的大部分无髓轴突网络中缓慢的、非同步的信号。这些新技术将分别用于STZ诱导的高血糖大鼠和Zucker糖尿病肥胖(ZDF)大鼠，作为1型和2型糖尿病的模型。在早期和晚期，电生理学结果将与DAN的组织病理学和形态计量学测量相关联。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发展，并将极大地提高我们区分有效治疗方法的能力，特别是当它们影响自主神经系统时。概述的研究是按顺序进行的。首先，我们将评估技术创新(例如，新的电极，非线性分析)，以确定在正常大鼠身上的一系列有用的措施；然后，被评为最佳的方法将是糖尿病模型，最后用于评估两种假定的治疗干预措施的效果(即ARI和脂溶硫胺素衍生物)。如果成功，这些研究将带来新的方法，更敏感的动物模型，以及对DAN功能缺陷的性质、程度、时间进程和治疗反应的更好理解。

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.