Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy: Is the source important?

Omega-3 多不饱和脂肪酸治疗糖尿病周围神经病变：来源重要吗？

• 批准号: 10447652
• 负责人: Mark A. Yorek
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447652
• 关键词: Address; Adverse effects; Affect; Afferent Neurons; Algae; Amputation; Anti-Inflammatory Agents; Behavioral; Blindness; Blood Circulation; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Caring; Cholesterol; Chronic; Chronic Disease; Clinical Trials; Complex; Complications of Diabetes Mellitus; Consumption; Cornea; Diabetes Mellitus; Dietary intake; Disease; Docosahexaenoic Acids; Dose; Eicosapentaenoic Acid; End stage renal failure; Equilibrium; Erythrocytes; Esters; Etiology; Event; Fatty Acids; Fish Oils; Fishes; Functional disorder; Goals; Greenland; Health Care Costs; Healthcare; Heart; Heavy Metals; High Density Lipoproteins; Hypertriglyceridemia; Industrialization; Inflammatory; Insulin-Dependent Diabetes Mellitus; Inuits; Limb structure; Measures; Modeling; Molecular Target; Motor; Nerve; Nerve Regeneration; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Obesity; Oils; Omega-3 Fatty Acids; Outcome; Overweight; Pain; Paresthesia; Pathologic; Pathway interactions; Patients; Peripheral Nervous System Diseases; Pharmacologic Substance; Physicians; Population; Prediabetes syndrome; Production; Property; Quality of life; Rattus; Research; Risk; Risk Factors; Rodent; Series; Serum; Skin; Source; Stress; Sum; Symptoms; Therapeutic; Type 2 diabetic; Ulcer; United States; Veterans; blood glucose regulation; cardioprotection; density; design; diabetic; diabetic rat; effective therapy; efficacious treatment; falls; glycemic control; human subject; improved; in vivo; indexing; menhaden; military veteran; mortality risk; nerve damage; nerve repair; patient population; preclinical study; relating to nervous system; repaired

In 2015, 9.4% of the United States population had diabetes and statistically about 50% of these patients will or already have developed diabetic peripheral neuropathy (DPN). This problem is even more critical in the veteran health care population with nearly 25% of veterans having diabetes, primarily type 2. In veterans diabetes is the leading cause of blindness, end-stage renal disease and non-trauma related amputations. The only treatment for DPN is glycemic control, which is ineffective in subjects with type 2 diabetes. Thus, there is a critical need of a treatment for DPN. Our studies have demonstrated that treating diabetic rodents with DPN with omega-3 polyunsaturated fatty acids (PUFA) derived from menhaden (fish) oil initiates nerve damage repair and reverses DPN. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the predominate omega-3 PUFA found in fish oil and are the precursors of E and D series resolvins, respectively, which have anti-inflammatory and neuroprotective properties. We have shown that these metabolites alone elicit repair of nerve damage caused by diabetes when administered endogenously in vivo. As we initiate plans to advance omega-3 PUFA to a clinical trial for DPN there remains several questions to be addressed. One common problem with the design of many of the previous clinical trials of omega-3 PUFA primarily for treatment of cardiovascular disease were that they failed to determine the circulating levels of omega-3 PUFA or their metabolites over the course of the study. For most of these studies it was unknown whether dosing was sufficient to make a therapeutic change in the omega-3 index, defined as the sum of EPA and DHA as a percentage of total fatty acids in red blood cells. Another poorly explored question has been what is the best source or composition of omega-3 PUFAs that will provide the most favorable and safe outcome? This is highlighted by the recent REDUCE-IT study that found that a 4 g daily dose of icosapent ethyl (ethyl ester of EPA) to have a statistical benefit on reducing ischemic events in subjects with hypertriglyceridemia. Was the significant outcome achieved in this study due to icosapent ethyl being a more effective source of omega-3 PUFA or use of a higher dose than many previous studies? We have shown that treating type 2 diabetic rats with fish oil that achieved an omega-3 PUFA concentration in serum that was obtained in human subjects treated with 4 g of fish oil per day is an efficacious treatment for DPN. However, is fish oil the best source of omega-3 PUFA for the treatment of DPN or are the ethyl ester derivatives of EPA and/or DHA more efficacious? Ethyl esters of EPA (Vascepa®) or the combination of EPA and DHA (Lovaza®) are pharmaceutical compounds and represent a highly purified and concentrated source of EPA and DHA and void of the less favorable compounds found in fish oil. Studies have shown that EPA and DHA and their metabolites have different molecular targets. Since the etiology of DPN is complex having both vascular and neural pathological pathways it is likely that a combination of EPA and DHA as found in Lovaza® will be needed for an effective treatment of DPN. Besides these pharmaceutical compounds are there other “healthy” alternatives to fish oil for the treatment of DPN? Commercially available algae's that primarily produce EPA or DHA may be another environmental friendly and safe source of omega-3 PUFA. The studies presented in this application will rigorously address the use of these alternative sources of omega-3 PUFA as a treatment for DPN and determine if omega-3 PUFA derived from pharmaceutical compounds i.e. ethyl ester derivatives of EPA or EPA/DHA or from industrial sources such as algae's that solely produce EPA or DHA free of cholesterol may be a better choice than fish oil. The proposed studies will be conducted in rat models of pre-diabetes and type 2 diabetes and will investigate translational endpoints including assessment of motor coordination and balance and function and density of sensory neurons to track the efficacy of omega-3 PUFA on peripheral neuropathy and the results correlated with the omega-3 index and circulating levels of omega-3 PUFA metabolites.

2015年，9.4%的美国人口患有糖尿病，据统计，其中约50%的患者将或 已患上糖尿病周围神经病变(DPN)。这个问题在中国更加严重。 退伍军人保健人群近25%的退伍军人患有糖尿病，主要是2型。在退伍军人中 糖尿病是导致失明、终末期肾病和非外伤性截肢的主要原因。这个 DPN的唯一治疗方法是血糖控制，这对2型糖尿病患者无效。因此，有一个 急需对DPN进行治疗。我们的研究表明，使用DPN治疗糖尿病啮齿动物 含有从鱼油中提取的omega-3多不饱和脂肪酸(PUFA)会引发神经损伤 修复和反转DPN。主要成分为二十碳五烯酸(EPA)和二十二碳六烯酸(DHA) 在鱼油中发现的omega-3多不饱和脂肪酸，分别是E系列和D系列拆分的前体，这两种拆分具有 具有抗炎和神经保护作用。我们已经证明，仅这些代谢物就能诱导修复 体内内源性给药时糖尿病引起的神经损伤。当我们开始计划推进 Omega-3多不饱和脂肪酸用于DPN的临床试验仍有几个问题需要解决。一个共同之处 欧米茄-3多不饱和脂肪酸先前的许多临床试验的设计存在问题，主要用于治疗 心血管疾病是他们未能确定循环中的omega-3多不饱和脂肪酸水平或他们的 研究过程中的代谢物。对于这些研究中的大多数，剂量是否是未知的 足以使omega-3指数发生治疗变化，该指数定义为EPA和DHA的总和 红细胞中总脂肪酸的百分比。另一个未被探索的问题是什么是最好的 将提供最有利和安全结果的omega-3多不饱和脂肪酸的来源或组成？这是 最近的Reduce-IT研究发现，每天服用4g二十碳辛乙酯(乙酸乙酯) EPA)在减少高甘油三酯血症受试者的缺血事件方面有统计上的好处。是不是 这项研究取得了重大成果，因为二十碳辛乙基是omega-3的更有效来源 多不饱和脂肪酸或使用比许多以前的研究更高的剂量？我们已经证明，治疗2型糖尿病大鼠 使用鱼油，其血清中的omega-3多不饱和脂肪酸浓度达到在人体中获得的浓度 每天服用4g鱼油是治疗DPN的有效方法。然而，鱼油是最好的来源吗？ 用于治疗DPN的omega-3多不饱和脂肪酸或EPA和/或DHA的乙酯衍生物 有效吗？EPA的乙酯(Vascepa®)或EPA和DHA的组合(Lovaza®)是 药物化合物，代表高度纯化和浓缩的EPA和DHA来源以及无效 在鱼油中发现的不太有利的化合物。研究表明，EPA和DHA及其代谢物 有不同的分子靶点。由于DPN的病因复杂，既有血管方面的，也有神经方面的 病理途径很可能需要在Lovaza®中发现的EPA和DHA的组合 治疗DPN的有效方法。除了这些药物化合物，还有其他“健康”的替代品吗？ 用鱼油治疗DPN吗？主要产生EPA或DHA的商业上可用的藻类可能是 另一种环境友好和安全的omega-3多不饱和脂肪酸来源。本申请中提供的研究 将严格解决这些omega-3多不饱和脂肪酸替代来源作为治疗DPN和 确定omega-3多不饱和脂肪酸是否来自药物化合物，即EPA的乙酯衍生物或 EPA/DHA或来自工业来源，如藻类，只生产不含胆固醇的EPA或DHA，可 是比鱼油更好的选择。拟议的研究将在糖尿病前期和类型的大鼠模型中进行。 2糖尿病，并将调查翻译终点，包括评估运动协调和平衡 以及感觉神经元的功能和密度来追踪omega-3多不饱和脂肪酸对周围神经病的疗效 这些结果与omega-3指数和循环中omega-3多不饱和脂肪酸代谢产物的水平相关。