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 已经患有糖尿病周围神经病变（DPN）。这个问题在 退伍军人医疗保健人群中近 25% 的退伍军人患有糖尿病，主要是 2 型糖尿病。 糖尿病是失明、终末期肾病和非创伤相关截肢的主要原因。这 DPN 的唯一治疗方法是控制血糖，这对 2 型糖尿病患者无效。因此，有一个 DPN 迫切需要治疗。我们的研究表明，用 DPN 治疗糖尿病啮齿动物 源自鲱鱼油的 omega-3 多不饱和脂肪酸 (PUFA) 会引发神经损伤 修复并逆转 DPN。二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是主要成分 鱼油中发现的 omega-3 PUFA 分别是 E 和 D 系列分解素的前体，它们具有 抗炎和神经保护特性。我们已经证明，这些代谢物本身就能引起修复 体内内源性给药时由糖尿病引起的神经损伤。当我们启动推进计划时 omega-3 PUFA 到 DPN 的临床试验仍有几个问题需要解决。一种常见的 之前许多 omega-3 PUFA 主要用于治疗以下疾病的临床试验的设计存在问题 心血管疾病的一个原因是他们未能确定 omega-3 PUFA 的循环水平或其 研究过程中的代谢。对于大多数这些研究，尚不清楚剂量是否是 足以对 omega-3 指数进行治疗性改变，该指数定义为 EPA 和 DHA 的总和 红细胞中总脂肪酸的百分比。另一个尚未探讨的问题是什么是最好的 omega-3 PUFA 的来源或成分将提供最有利和最安全的结果？这是 最近的 REDUCE-IT 研究强调了这一点，该研究发现每日 4 克剂量的二十碳五烯乙酯（二十碳五烯乙酯） EPA）对减少高甘油三酯血症受试者的缺血事件具有统计益处。是 由于二十碳五烯乙酯是 omega-3 的更有效来源，因此本研究取得了重大成果 PUFA 或使用比许多先前研究更高的剂量？我们已经证明治疗 2 型糖尿病大鼠 使用鱼油，在人类受试者的血清中达到 omega-3 PUFA 浓度 每天服用 4 克鱼油可有效治疗 DPN。然而，鱼油是最好的来源吗？ 用于治疗 DPN 的 omega-3 PUFA 或 EPA 和/或 DHA 的乙酯衍生物 更多 有效果吗？ EPA 乙酯 (Vascepa®) 或 EPA 和 DHA 的组合 (Lovaza®) 药物化合物，代表高度纯化和浓缩的 EPA 和 DHA 来源，并且无效 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，既有血管性的，也有神经性的。 病理途径很可能需要 Lovaza® 中发现的 EPA 和 DHA 组合 DPN 的有效治疗方法。除了这些药物化合物之外，还有其他“健康”的替代品 鱼油可以治疗 DPN？主要产生 EPA 或 DHA 的市售藻类可能是 另一种环保且安全的 omega-3 PUFA 来源。本申请中提出的研究 将严格解决使用这些 omega-3 PUFA 替代来源治疗 DPN 的问题 确定 omega-3 PUFA 是否源自药物化合物，即 EPA 的乙酯衍生物或 EPA/DHA 或来自工业来源（例如仅生产不含胆固醇的 EPA 或 DHA 的藻类）可能 是比鱼油更好的选择。拟议的研究将在糖尿病前期和糖尿病类型的大鼠模型中进行 2 型糖尿病，并将研究转化终点，包括评估运动协调和平衡 以及感觉神经元的功能和密度，以追踪 omega-3 PUFA 对周围神经病变的疗效 结果与 omega-3 指数和 omega-3 PUFA 代谢物的循环水平相关。