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，据统计，这些患者中约有50%将或 糖尿病周围神经病变（DPN）。这一问题在世界范围内更为严重。 退伍军人医疗保健人群，近25%的退伍军人患有糖尿病，主要是2型糖尿病。在退伍军人 糖尿病是失明、末期肾病和非创伤性截肢的主要原因。的 DPN的唯一治疗是血糖控制，这在2型糖尿病患者中无效。由此可见，有一 急需治疗DPN。我们的研究表明，用DPN治疗糖尿病啮齿动物 含有从鲱鱼油中提取的omega-3多不饱和脂肪酸（PUFA）， 修复和逆转DPN。二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是主要的 鱼油中发现的omega-3 PUFA，分别是E和D系列消退素的前体， 抗炎和神经保护特性。我们已经证明，这些代谢物单独引起修复， 糖尿病在体内内源性给药时引起的神经损伤。当我们开始计划 omega-3 PUFA用于DPN的临床试验，仍有几个问题需要解决。一个共同 许多以前的omega-3 PUFA临床试验的设计问题主要是用于治疗 心血管疾病是他们未能确定循环水平的ω-3多不饱和脂肪酸或其 在研究过程中的代谢物。对于大多数这些研究，尚不清楚给药是否 足以使欧米茄-3指数发生治疗性变化，欧米茄-3指数定义为EPA和DHA的总和， 红细胞中总脂肪酸的百分比。另一个探索不足的问题是什么是最好的 omega-3多不饱和脂肪酸的来源或组成，将提供最有利和安全的结果？这是 最近的REDUCE-IT研究强调了这一点，该研究发现，每天4g剂量的二十碳五烯酸乙酯（ EPA）在减少高甘油三酯血症受试者的缺血事件方面具有统计学获益。是 由于二十碳五烯酸乙酯是omega-3更有效来源， 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 鱼油达到人体血清中omega-3 PUFA浓度， 每天用4g鱼油治疗是DPN的有效治疗。然而，鱼油是最好的来源吗？ 用于治疗DPN的ω-3 PUFA或者是EPA和/或DHA的乙酯衍生物， 灵验？EPA的乙酯（Vascepa®）或EPA和DHA的组合（Lovaza®）是 作为一种高纯度和高浓度的EPA和DHA的来源， 鱼油中不太有利的化合物。研究表明，EPA和DHA及其代谢产物 具有不同的分子靶点。由于DPN的病因复杂， 因此，在某些病理途径中，可能需要Lovaza®中发现的EPA和DHA的组合， DPN的有效治疗。除了这些药物化合物，还有其他“健康”的替代品吗？ 鱼油治疗糖尿病周围神经病变主要产生EPA或DHA的市售藻类可以是 另一种环境友好和安全的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替代来源作为DPN治疗的问题， 确定ω-3 PUFA是否来源于药物化合物，即EPA的乙酯衍生物，或 EPA/DHA或来自工业来源如仅产生不含胆固醇的EPA或DHA的藻类， 是比鱼油更好的选择。拟议的研究将在糖尿病前期和型糖尿病的大鼠模型中进行。 2型糖尿病并将研究转化终点，包括运动协调和平衡评估 以及感觉神经元的功能和密度，以跟踪omega-3 PUFA对周围神经病变的功效 结果与omega-3指数和omega-3多不饱和脂肪酸代谢物的循环水平相关。