Intermittent cold exposure in diabetic polyneuropathy

描述(申请人提供)：至少70%的糖尿病患者会出现多发性神经病变及其相关的疾病，包括感觉丧失、疼痛、行动不便、溃疡，甚至是受影响的肢体截肢。糖尿病多神经病变(DP)的发病机制非常复杂，组织缺血、炎症、蛋白激酶C激活、蛋白糖化等都被认为是重要的机制，尽管其他因素也可能起作用。一个可能被忽视的因素可能对DP的发病机制有重要影响，那就是温度。即使对远端肢体进行相对温和的降温，也可能会加剧组织缺血，增加免疫复合物的沉积，导致蛋白激酶C的进一步激活，并增加蛋白糖基化。由于DP患者的远端体温调节受损，神经病变可能会进一步恶化，神经和血管功能障碍会导致体温调节进一步受损，从而导致DP本身进展更快。尽管有这种潜在的重要联系，但仅获得了一些有限的流行病学数据，这表明生活在较冷气候的患者比生活在较温暖气候的患者有更高的DP发病率。本研究的目的是研究温度对大鼠糖尿病发展的影响，以确定：1.间歇降温是如何影响神经健康的；2.这种影响是通过什么潜在机制发生的。我们计划通过三个具体目标来实现这一目标。所有这三个目标都将涉及对一组健康大鼠和一组注射链脲佐菌素的糖尿病大鼠的研究。每组大鼠的不同亚组将暴露在稳定的室温(~23℃)、间歇性凉爽温度(~16℃)或间歇性寒冷(~10℃)中16周。在第一个目标中，我们将通过行为和电生理方法评估和比较每组患者的神经功能随时间的变化。在第二个目标中，我们将在为期16周的研究结束时评估微血管、神经和皮肤的微观病理。在第三个目标中，我们将使用ELISA和微阵列技术来确定寒冷暴露如何影响这些动物的分子标记。如果这些实验能够证明寒冷暴露与DP的发展之间的关系，那么未来对动物和人类受试者的研究可能有助于进一步阐明这种相互作用发生的具体机制。但更重要的是，这些结果将表明，远端肢体温度的稳定可能有助于减缓这种衰弱疾病的进展。

DESCRIPTION (provided by applicant): At least 70% of all patients with diabetes mellitus will develop polyneuropathy and its associated morbidities, including loss of sensation, pain, impaired mobility, ulcers and even amputation of affected extremities. The pathogenesis of diabetic polyneuropathy (DP) is very complex, with tissue ischemia, inflammation, protein kinase C activation, protein glycation all having been identified as important mechanisms, although other factors are also likely to play a role. One potentially overlooked factor which may have an important influence on the pathogenesis of DP is that of temperature. Even relatively mild cooling of the distal extremities could enhance tissue ischemia, augment immune complex deposition, lead to further activation of protein kinase C, and increase protein glycation. Given the impaired distal thermoregulation of individuals with DP, a cycle of worsening neuropathy may develop where further nerve and vascular dysfunction lead to further impairment in thermoregulation, causing a more rapid progression of the DP itself. Despite this potentially important connection, only some limited epidemiological has been obtained which suggests that patients living in colder climates have a higher incidence of DP than those living in warmer climates. The goal of this proposal is to examine the effect of temperature on the development of DP in rats in order to determine: 1. how intermittent cooling impacts nerve health; and 2. through what potential mechanisms such effects occur. We plan to achieve this via three specific aims. All three aims will involve the study of a group of healthy rats and a group of streptozotocin-injected diabetic rats. Subsets of rats from each of these groups will be exposed to either steady room temperature (~23¿C), intermittent cool temperature (~16¿C), or intermittent cold (~10¿C) for 16 weeks. In the first aim, we will assess and compare how nerve function changes over time in each group, as measured by behavioral and electrophysiological methods. In the second aim, we will assess the microscopic pathology of the microvasculature, nerve, and skin at the conclusion of the 16-week study period. In the third aim, we will determine how cold-exposure affects molecular markers in these animals, using ELISA and microarray techniques. If these experiments are able to demonstrate a relationship between cold-exposure and the development of DP, then future studies in animals and human subjects may help further elucidate the specific mechanisms by which this interaction occurs. But more importantly, such results would indicate that stabilization of distal limb temperature may help slow the progression of this debilitating disorder.