Effects of Fish Oil ± Salsalate on the Omega-3 Index and the Circulating Lipodome of Omega-3 Polyunsaturated Fatty Acid Metabolites in Patients with Type 2 Diabetes and Diabetic Neuropathy

鱼油±水杨酸对 2 型糖尿病和糖尿病神经病变患者 Omega-3 指数和 Omega-3 多不饱和脂肪酸代谢物循环脂质组的影响

• 批准号: 10296769
• 负责人: RODICA BUSUI (POP-BUSUI)
• 金额: $ 65.93万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296769
• 关键词: Address; Affect; Amputation; Anti-Inflammatory Agents; Aspirin; Automobile Driving; Biological Assay; C-reactive protein; Chronic; Clinical; Clinical Trials; Complication; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease; Docosahexaenoic Acids; Dose; Effectiveness; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Fatty Acids; Fish Oils; Goals; Health Care Costs; Healthcare Systems; Human; In Vitro; Inflammation; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-6; Iowa; Knowledge; Laboratories; Lead; Limb structure; Liquid Chromatography; Measures; Mediator of activation protein; Menhaden oil; Metabolic; Michigan; Nerve Regeneration; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Omega-3 Fatty Acids; Outcome; Oxidative Stress; Pain; Pain management; Paresthesia; Participant; Patients; Peripheral Nervous System Diseases; Phase II/III Trial; Physical Function; Physicians; Population; Production; Property; Quality of life; Research; Risk; Risk Factors; Rodent; Safety; Salicylic Acids; Series; Sum; Supplementation; Symptoms; TNF gene; Testing; Therapeutic; Translating; Ulcer; Universities; Work; base; blood glucose regulation; chemokine; cost; cytokine; design; diabetic; effective therapy; efficacious treatment; factor A; glycemic control; human subject; improved; in vivo; indexing; inflammatory marker; insulin sensitivity; lipid mediator; lipidomics; menhaden; mortality risk; nerve damage; nerve repair; neurite growth; patient population; personalized approach; pre-clinical; preclinical study; repaired; response; salicylsalicylic acid; side effect; success; tandem mass spectrometry; targeted treatment

Peripheral neuropathy, the most prevalent chronic complication of diabetes may affect up to 50% of patients and critically contributes to increased pain and risk of amputations, lower physical functioning, increased daily living burden, reduced quality of life, increased health care costs, and high mortality risk. Although intensive glucose control was shown to delay the onset and progression of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes, similar evidence is not available for the very vast majority of patients who have type 2 diabetes (T2D). In spite of continuous research a disease modifying therapy to reverse human DPN is still not available. Work in our laboratories has provided evidence that omega-3 polyunsaturated fatty acids (PUFA) found in fish oil in combination with salsalate may be an effective treatment for DPN. Our pre-clinical studies have shown that fish oil and salsalate slows progression of DPN and initiates nerve damage repair and reverses DPN . We have also demonstrated that E and D series resolvins, metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, reverses DPN to a similar extent as fish oil. These data provides the rationale to advance the fish oil-salsalate combination to DPN clinical trials. The studies proposed in this application are the first step in this endeavor. Using participants with T2D and DPN we will initially establish the most efficient dose of fish oil that will increase the omega-3 index (defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells) to at least 8 – 12% presumed to be therapeutic. Next, we will combine fish oil and salsalate to examine their effect on the production of pro-resolving metabolites derived from EPA and DHA. We hypothesize that fish oil in a concentration dependent manner will increase the omega-3 index to therapeutic levels independent of salsalate. We also hypothesize that combining fish oil and salsalate vs. fish oil alone will more effectively increase the circulating pro-resolving mediators of omega-3 PUFA and reduce markers of inflammation to a greater extent than fish oil alone. The lipidomics of omega-3 PUFA in human subjects has been understudied and not at all in subjects with diabetes and DPN. Limited studies in normal human subjects taking fish oil have demonstrated considerable variability in circulating levels of omega-3 PUFA and this variability could have an impact on their metabolic fate. The studies proposed will address this limitation and guide us in selecting the most effective and safe combination dose of fish oil and salsalate for increasing the omega-3 index to a therapeutic level and maximize production of pro-resolving lipid mediators. This will lead to design of a disease modifying trial for DPN, with the potential to improve the quality of life for all patients with diabetes. The excellent safety profiles of fish oil and salsalate make them an attractive choice for long-term clinical use.

周围神经病，糖尿病最普遍的慢性并发症可能会影响多达50％ 患者和严重的疼痛和截肢风险增加，身体降低 功能，日常生活增加，生活质量减少，医疗保健成本的增加和高 死亡风险。尽管强烈的葡萄糖控制已显示出延迟的发作和进展 1型糖尿病患者的糖尿病外周神经病（DPN），没有类似的证据 对于绝大多数患有2型糖尿病（T2D）的患者。尽管有持续的研究 仍无法使用修改人DPN的疾病疗法。在我们的实验室工作 提供的证据表明，在鱼油中发现的omega-3多不饱和脂肪酸（PUFA） 与salsalate有关DPN的有效治疗方法。我们的临床前研究表明鱼油 salsalate放慢了DPN的进展，并启动神经损伤修复并逆转DPN。我们 还证明了E和D系列分辨蛋白，Eicosapentaenoic酸的代谢产物（EPA） 和二十六烯酸（DHA）分别将DPN逆转与鱼油相似。这些 数据提供了将鱼油 - 盐盐组合推向DPN临床试验的基本原理。这 在本应用中提出的研究是这项工作的第一步。使用T2D的参与者 DPN我们最初将建立最有效的鱼油，以增加omega-3指数 （定义为EPA和DHA的总和，是红细胞中总脂肪酸的百分比）至少 8 - 12％是治疗。接下来，我们将结合鱼油和咸水，以检查它们 对源自EPA和DHA衍生的促进分泌代谢产物的产生的影响。我们假设这一点 以浓度依赖的鱼油将omega-3指数提高到治疗水平 独立于salsalate。我们还假设将鱼油和咸水与鱼油相结合 将更有效地增加Omega-3 PUFA的循环促进介质介体并减少 炎症的标记比单独的鱼油更大。 Omega-3 PUFA的脂质组学 人类受试者已被理解，根本没有在患有糖尿病和DPN的受试者中。有限的 对服用鱼油的正常受试者的研究表明， Omega-3 PUFA的循环水平和这种变异性可能会影响其代谢命运。 提出的研究将解决这一限制，并指导我们选择最有效，最安全的 鱼油和萨拉酸盐的组合剂量，将omega-3指数提高到治疗水平和 最大化促脂质脂质介质的产生。这将导致疾病修饰的设计 DPN试验，有可能改善所有糖尿病患者的生活质量。优秀 鱼油和咸水的安全概况使它们成为长期临床使用的吸引人选择。