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: 10558558
• 负责人: RODICA BUSUI (POP-BUSUI)
• 金额: $ 64.84万
• 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/10558558
• 关键词: 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; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-6; Iowa; Knowledge; Laboratories; Limb structure; Liquid Chromatography; Measures; Mediator; 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; Symptoms; TNF gene; Testing; Therapeutic; Translating; Ulcer; Universities; Work; blood glucose regulation; chemokine; cost; cytokine; design; diabetic; effective therapy; efficacious treatment; fatty acid supplementation; glycemic control; human subject; improved; in vivo; indexing; inflammatory marker; insulin sensitivity; lipid mediator; lipidomics; mortality risk; nerve damage; nerve repair; neurite growth; neuroprotection; 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.

周围神经病变是糖尿病最常见的慢性并发症，可能影响高达 50% 的人 患者并严重加剧疼痛和截肢风险，降低体力 功能、日常生活负担增加、生活质量下降、医疗保健费用增加以及高 尽管强化血糖控制已被证明可以延缓糖尿病的发生和进展。 1 型糖尿病患者的糖尿病周围神经病变 (DPN)，没有类似的证据 尽管研究不断进行，但对于绝大多数 2 型糖尿病 (T2D) 患者来说。 我们的实验室尚未开展逆转人类 DPN 的疾病修饰疗法。 提供证据表明鱼油中含有 omega-3 多不饱和脂肪酸 (PUFA) 我们的临床前研究表明，鱼油可能是 DPN 的有效治疗方法。 水杨酸可减缓 DPN 的进展并启动神经损伤修复并逆转 DPN。 还证明了 E 和 D 系列分解素，二十碳五烯酸 (EPA) 的代谢物 和二十二碳六烯酸 (DHA) 分别可以与鱼油类似的程度逆转 DPN。 数据为将鱼油-水杨酸组合推进 DPN 临床试验提供了依据。 本申请中提出的研究是使用患有 T2D 的参与者的第一步。 DPN 我们将首先确定最有效的鱼油剂量，以提高 omega-3 指数 （定义为 EPA 和 DHA 的总和，以红细胞中总脂肪酸的百分比表示）至少 8 – 12% 被认为具有治疗作用 接下来，我们将结合鱼油和水杨酸来检查它们的效果。 对 EPA 和 DHA 衍生的促分解代谢物产生的影响。 鱼油以依赖浓度的方式将 omega-3 指数提高至治疗水平 我们还发现，鱼油和水杨酸的组合与单独的鱼油的比较。 将更有效地增加 omega-3 PUFA 的循环促分解介质并减少 与单独使用鱼油相比，Omega-3 PUFA 的脂质组学效果更强。 人类受试者的研究还不够充分，而且根本没有在糖尿病和 DPN 受限的受试者中进行研究。 对服用鱼油的正常人类受试者的研究表明， omega-3 PUFA 的循环水平和这种变异性可能会影响其代谢命运。 拟议的研究将解决这一局限性并指导我们选择最有效和最安全的 鱼油和水杨酸的组合剂量，用于将 omega-3 指数提高到治疗水平，以及 最大限度地产生促解决脂质介质这将导致疾病修饰的设计。 DPN 试验有望改善所有糖尿病患者的生活质量。 鱼油和水杨酸的安全性使其成为长期临床使用的有吸引力的选择。