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

糖尿病神经病变：角膜神经的功能结构评估损伤修复

• 批准号: 10339313
• 负责人: RANDY H. KARDON
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339313
• 关键词: Affect; Blinking; Caring; Climacteric; Clinical; Clinical Research; Clinical Trials; Complications of Diabetes Mellitus; Confocal Microscopy; Consumption; Cornea; Development; Diabetes Mellitus; Diabetic Neuropathies; Diagnosis; Diet; Dietary intake; Disease; Docosahexaenoic Acids; Early Diagnosis; Eicosapentaenoic Acid; Epidemic; Epithelial; Esthesia; Eyedrops; Family; Feasibility Studies; Fish Oils; Funding; General Population; Goals; Health Benefit; Health Care Costs; Healthcare Systems; Hyperglycemia; Impairment; Limb structure; Lower Extremity; Metabolic syndrome; Methods; Morphology; N-3 polyunsaturated fatty acid; Natural regeneration; Nerve; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Obesity; Omega-3 Fatty Acids; Ophthalmic examination and evaluation; Oral; Outcome Measure; Overweight; Pain; Pain management; Paresthesia; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Physicians; Polyunsaturated Fatty Acids; Population; Prediabetes syndrome; Prevalence; Primary Health Care; Quality of life; Rattus; Reflex action; Research; Role; Screening procedure; Strabismus; Structure; Surrogate Markers; Symptoms; Testing; Time; Topical application; Type 2 diabetic; Ulcer; Veterans; Visit; behavior test; behavioral response; blink reflexes; capsule; clinical Diagnosis; corneal epithelium; corneal regeneration; cost; cost effective treatment; density; diabetic; diabetic rat; diet-induced obesity; effective therapy; efficacy evaluation; fall injury; fall risk; glucose tolerance; glycemic control; high risk; human subject; impaired glucose tolerance; improved; improved outcome; injury and repair; interest; limb amputation; loss of function; military veteran; nerve damage; novel; peripheral nerve damage; preclinical study; preservation; receptor; repaired; response; screening; standard of care; statistics; western diet

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.

周围神经病变（PN）影响约50%的糖尿病人群。症状包括疼痛， 四肢麻木、感觉异常和溃疡，PN是非创伤性的主要原因 截肢2010年，退伍军人管理局医疗保健系统花费了2.06亿美元用于照顾退伍军人，这些退伍军人的收入较低， 由于糖尿病引起的PN而截肢。这一统计数字说明了这种疾病的影响， 它对退伍军人及其家属的生活质量和功能以及大部分人的生活质量和功能产生了毁灭性的影响。 对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。 在某些实施方案中，糖尿病可导致高血糖症，并且可在患有前驱糖尿病和葡萄糖耐量受损的受试者中检测到。这些 受试者通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，使他们处于发展PN和2型糖尿病的高风险中。的 PN的早期诊断具有挑战性，除了控制血糖外，没有其他治疗方法， 对2型糖尿病无效。随着肥胖和2型糖尿病的流行， 退伍军人和普通人群迫切需要改善PN的诊断，并找到一种治疗方法。 治疗本提案的目标是调查这两个重要问题。 与许多疾病一样，改善PN治疗的关键是早期发现。目前，临床诊断 对于PN是主观的，大多数退伍军人只有在出现症状后才接受PN的诊断， 先进的PN如果新的治疗旨在保留神经和刺激神经， 再生是成功的。最近，角膜上皮下神经的丧失被认为是 PN替代标记物。然而，利用角膜共焦显微镜来评估角膜神经的丧失， 检测PN的常规方法将具有挑战性。因此，我们开发了一个客观的测试， 角膜敏感性作为检测PN的简单筛选方法。该方法采用了使用 高渗滴眼液，激活角膜中的瞬时受体通道-8受体，引起反射性眨眼 如果神经完好就眯着眼即使在高血糖症发作之前，即糖尿病前期， 周围神经失去感觉，并且对角膜刺激的反射反应较少。发展 可在每年一次的常规临床初级保健访视期间进行的PN早期检测方法，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，我们还将扩大我们的检查安全和成本效益的治疗，以减缓 进展和逆转PN引起的神经损伤，从而为退伍军人提供解决方案 毁灭性的问题我们首次引入鱼油作为VA患者PN的治疗方法， 在最后一个资助期内，我们将继续进行这些研究，最终进行一项可行性研究， 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） 鱼油中常见的多不饱和脂肪酸，主要是二十碳五烯酸， 二十二碳六烯酸可能是糖尿病前期和糖尿病相关PN的有效治疗方法。 鱼油中的n-3多不饱和脂肪酸在西方饮食中的消费量很低， n-6多不饱和脂肪酸的消耗增加。许多临床研究表明潜在的好处 n-3多不饱和脂肪酸的消耗对各种疾病。因此，有一个巨大的兴趣， 在增加作为胶囊的n-3多不饱和脂肪酸的饮食摄入方面， 选择可能受益最多的临床人群。尽管n-3多不饱和脂肪酸的健康益处 脂肪酸已被广泛研究，它们作为糖尿病并发症的潜在治疗方法，包括 PN，尚未得到深入研究。本申请中提出的研究将填补这一空白， 提供推进临床试验n-3多不饱和脂肪酸（即鱼油）治疗PN的依据。