Diabetic Neuropathy: Function-Structure of Corneal Nerves to Assess Injury-Repair

周围神经病变(PN)影响约50%的糖尿病人群。症状包括疼痛， 肢体麻木、感觉异常和溃疡是非创伤性的主要原因 截肢手术。2010年，退伍军人医疗保健系统在照顾退伍军人方面花费了2.06亿美元，这些退伍军人的 糖尿病引起的PN导致的肢体截肢。这个单一的统计数字说明了这种疾病和 它对退伍军人及其家人以及广大民众的生活质量和功能具有毁灭性的影响 退伍军人医疗保健系统的成本负担。我们现在知道PN可以在发病前发展。 高血糖，并可在糖尿病前期和糖耐量受损的受试者中检测到。这些 受试者经常超重，并有代谢综合征的症状。最近的统计数据表明，72%的 退伍军人超重或肥胖，这使他们处于发展为PN和2型糖尿病的高风险。这个 PN的早期诊断具有挑战性，除了血糖控制外，没有可用的治疗方法。 对2型糖尿病无效。随着肥胖症和2型糖尿病在两国的流行水平 退伍军人和普通人群迫切需要提高PN的诊断水平，并找到一种 治疗。这项提案的目标是调查这两个重要问题。 像许多疾病一样，改善PN治疗的关键是及早发现。目前，临床诊断 由于PN是主观的，大多数退伍军人只有在出现症状和 高级PN。如果以保留神经和刺激为目的的新疗法，则需要早期诊断PN 再生是成功的。最近，角膜上皮下神经的丢失被认为是一种 PN的代理标记。然而，利用角膜共聚焦显微镜来评估角膜神经的丢失 检测PN的常规方法将是具有挑战性的。因此，我们开发了一种依赖于 角膜敏感度作为检测PN的简便筛选方法。该方法使用了一个 高渗滴眼液激活角膜瞬时受体通道-8受体引起反射性眨眼 如果神经完好无损，还会眯起眼睛。甚至在高血糖发作之前，即糖尿病前期，就已经受损 周围神经失去知觉，对角膜刺激的反射反应较少。开发一种 一种早期检测PN的方法，可在每年的常规临床初级保健访问或 眼科检查将提高糖尿病退伍军人的护理标准。 在这项申请中，我们还将研究一种安全且经济有效的治疗方法来减缓 从而为退伍军人提供了一种解决方案 毁灭性的问题。我们首次引入鱼油作为治疗退伍军人退伍军人病的一种方法，支持的临床前研究 最后一个资助期，并将继续这些研究，最终形成治疗人类 患有2型糖尿病和神经病变的受试者。我们之前的研究表明，长链omega-3(n-3) 常见于鱼油中的多不饱和脂肪酸，主要是二十碳五烯酸和 二十二碳六烯酸可能是治疗与糖尿病前期和糖尿病相关的PN的有效方法。 在西方饮食中，在鱼油中发现的n-3多不饱和脂肪酸的消费量很低，因为历史上 增加n-6多不饱和脂肪酸的消费量。大量的临床研究表明潜在的益处 研究了n-3多不饱和脂肪酸对各种疾病的影响。因此，存在着极大的兴趣 增加n-3多不饱和脂肪酸胶囊的膳食摄入量 选择可能受益最大的临床人群。即使n-3多不饱和脂肪酸的健康益处 脂肪酸已经得到了广泛的研究，它们作为糖尿病并发症的潜在治疗方法，包括 Pn，还没有得到深入的研究。本申请中提出的研究将填补这一空白，并将 为推进临床试验n-3多不饱和脂肪酸，即作为治疗PN的鱼油提供理论依据。

Peripheral neuropathy (PN) affects about 50% of the diabetic population. The symptoms range from pain, numbness, paresthesia and ulceration in the extremities and PN is the major cause of non-traumatic amputations. In 2010 the VA healthcare system spent $206 million on care of veterans that received lower- limb amputations due to diabetes-induced PN. This single statistic illustrates the impact of this disease and the devastating effect it has on the quality of life and functioning of veterans and their families as well as the large cost burden on the VA healthcare system. We now know that PN can develop before the onset of hyperglycemia and can be detected in subjects with pre-diabetes and impaired glucose tolerance. These subjects are often overweight with symptoms of metabolic syndrome. Recent statistics indicate that 72% of all Veterans are overweight or obese placing them at high risk of developing PN and type 2 diabetes. The diagnosis of PN in its early stages is challenging and no treatment is available, besides glycemic control, which is ineffective for type 2 diabetes. With the prevalence of obesity and type 2 diabetes at epidemic levels in both the veteran and general populations there is a critical need for improving the diagnosis of PN and finding a treatment. The goals of this proposal are to investigate both of these important issues. A key to improving treatment of PN like many disorders is early detection. Presently, the clinical diagnosis for PN is subjective with most veterans receiving a diagnosis of PN only after presenting with symptoms and advanced PN. Earlier diagnosis of PN is needed if new treatments aimed at preserving nerves and stimulating regeneration is to be successful. Recently, loss of sub-epithelial corneal nerves has been promoted as being a surrogate marker of PN. However, utilizing corneal confocal microscopy to evaluate loss of corneal nerves as a routine method to detect PN would be challenging. Thus, we have developed an objective test relying on corneal sensitivity as a simple screening method for detecting PN. The method employs the use of a hyperosmolar eye drop to activate transient receptor channel-8 receptors in the cornea to cause reflex blinking and squinting if the nerves are intact. Even before the onset of hyperglycemia, i.e. pre-diabetes, damaged peripheral nerves lose sensation, and will have less reflex response to corneal stimulation. Development of a method of early detection of PN that can be performed annually during a routine clinical primary care visit or eye examination would improve the standard of care for veterans with diabetes. In this application we will also extend our examination of a safe and cost effective treatment to slow progression and reverse nerve damage caused by PN, thereby providing veterans a solution for this devastating problem. We first introduced fish oil as a treatment of PN in VA supported pre-clinical studies in the last funding period and will continue these studies culminating in a feasibility study for treating human subjects with type 2 diabetes and neuropathy. Our previous studies suggest that long-chain omega-3 (n-3) polyunsaturated fatty acids that are commonly found in fish oils, primarily eicosapentaenoic acid and docosahexaenoic acid, may be an effective treatment for PN associated with pre-diabetes and diabetes. Consumption of n-3 polyunsaturated fatty acids found in fish oils is low in the Western diet due to historically increased consumption of n-6 polyunsaturated fatty acids. Numerous clinical studies suggest potential benefits of n-3 polyunsaturated fatty acid consumption on various diseases. Therefore, there is a tremendous interest in increasing the dietary intake of n-3 polyunsaturated fatty acids as a capsule for the general public and for select clinical populations that may benefit the most. Even though the health benefits of n-3 polyunsaturated fatty acids have been widely examined, their role as a potential treatment for diabetes complications, including PN, have not been thoroughly studied. The studies presented in this application will fill this void and will provide rationale to advance to clinical trials n-3 polyunsaturated fatty acids, i.e. fish oils as a treatment for PN.