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: 10610377
• 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/10610377
• 关键词: Acids; Address; Adverse effects; Affect; Afferent Neurons; Algae; Amputation; Anti-Inflammatory Agents; Behavioral; Blindness; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Caring; Cholesterol; Chronic; Chronic Disease; Circulation; 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; Friends; Functional disorder; Goals; Greenland; Health Care Costs; Healthcare; Heart; Heavy Metals; High Density Lipoproteins; Hypertriglyceridemia; Industrialization; Inflammatory; Insulin-Dependent Diabetes Mellitus; Inuits; Ischemia; Limb structure; Measures; Menhaden oil; 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; neural; neuroprotection; patient population; preclinical study; 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，统计上约有50％的患者将或 已经开发了糖尿病周围神经病（DPN）。这个问题在 老兵卫生保健人口，近25％的退伍军人患有糖尿病，主要2型。 糖尿病是失明，终末期肾脏疾病和非创伤截肢的主要原因。 DPN的仅治疗是血糖控制，它在2型糖尿病患者中无效。那有一个 对DPN治疗的迫切需要。我们的研究表明，用DPN治疗糖尿病啮齿动物 源自Menhaden（Fish）油的omega-3多不饱和脂肪酸（PUFA）启动神经损伤 维修和逆转DPN。 eicosapontaenoic酸（EPA）和二十二烯酸（DHA）是主要的 在鱼油中发现的Omega-3 PUFA，分别是E和D系列分辨率的前体 抗炎和神经保护特性。我们已经表明，仅这些代谢产生了 当体内内源性施用糖尿病引起的神经损伤。当我们启动计划时 Omega-3 PUFA进行DPN的临床试验，仍有几个问题要解决。一个常见 omega-3 PUFA主要的许多先前临床试验的设计问题 心血管疾病是他们未能确定omega-3 PUFA或其其循环水平 在整个研究过程中的代谢产物。对于大多数这些研究，尚不清楚给药是否是 足以在Omega-3指数中进行治疗性更改，该指数定义为EPA和DHA的总和 红细胞中总脂肪酸的百分比。另一个探讨的问题是最好的 Omega-3 Pufas的来源或组成将提供最有利和安全的结果？这是 最近的简化研究强调了每日4 g剂量的ICOSAPENT乙基（乙基酯的乙酯） EPA）具有减少高甘油三酯血症受试者缺血事件的统计益处。是 在这项研究中取得的重大结果是由于脱糖乙基是omega-3的更有效来源 PUFA还是使用更高的剂量？我们已经表明治疗2型糖尿病大鼠 通过在人类受试者中获得的血清中omega-3 PUFA浓度达到的鱼油 每天用4克鱼油处理是DPN的有效治疗方法。但是，鱼油是最好的来源 omega-3 PUFA用于治疗DPN或EPA和/或DHA的乙基酯衍生物更多 有效？ EPA（VASCEPA®）的乙基酯或EPA和DHA（Lovaza®）的组合是 药物化合物，代表EPA和DHA的高度纯化和浓缩来源 在鱼油中发现的不太有利的化合物中。研究表明，EPA和DHA及其代谢物 具有不同的分子靶标。由于DPN的病因很复杂，具有血管和中性 病理途径可能需要在Lovaza®中发现的EPA和DHA的组合 DPN的有效处理。除这些药物外，还有其他“健康”替代品 钓鱼以治疗DPN？主要产生EPA或DHA的市售藻类可能是 Omega-3 PUFA的另一个环保且安全的来源。本应用程序中介绍的研究 将严格解决omega-3 PUFA的这些替代来源作为DPN和 确定omega-3 PUFA是否源自药物化合物，即EPA或EPA的乙基酯衍生物 EPA/DHA或来自藻类等工业来源，仅产生EPA或DHA无胆固醇可能 比鱼油更好。拟议的研究将在糖尿病前的大鼠模型和类型的大鼠模型中进行 2种糖尿病，并将调查转化终点，包括评估运动协调和平衡 感觉神经元的功能和密度跟踪omega-3 PUFA在周围神经病上的效率 结果与omega-3指数和欧米茄-3 PUFA代谢物的循环水平相关。