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

周围神经病变是糖尿病最常见的慢性并发症，可影响高达50%的 患者和严重有助于增加疼痛和截肢的风险，降低身体 功能，增加日常生活负担，降低生活质量，增加医疗保健费用， 死亡风险。虽然强化血糖控制可以延缓糖尿病的发作和进展， 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 2型糖尿病（T2 D）的发病率有多大？尽管不断的研究 逆转人DPN的疾病改善疗法仍然不可用。我们实验室的工作 提供证据表明，鱼油中发现的omega-3多不饱和脂肪酸（PUFA） 双水杨酸可能是治疗DPN的有效方法。我们的临床前研究表明鱼油 双水杨酸可减缓DPN的进展并启动神经损伤修复和逆转DPN。我们 还证明了E和D系列消退素，二十碳五烯酸（EPA）的代谢产物， 和二十二碳六烯酸（DHA）逆转DPN的程度与鱼油相似。这些 数据提供了将鱼油-双水杨酸盐组合推进到DPN临床试验的基本原理。的 本申请中提出的研究是这一奋进的第一步。使用患有T2 D的参与者， DPN我们将初步确定最有效的鱼油剂量，这将增加欧米茄-3指数 （定义为EPA和DHA的总和，作为红细胞中总脂肪酸的百分比）至少 8 - 12%被认为是治疗性的。接下来，我们将结合联合收割机鱼油和双水杨酸盐，以检查其 对源自EPA和DHA的促分解代谢物的产生的影响。我们假设 鱼油以浓度依赖的方式将欧米茄-3指数提高到治疗水平 独立于salsalate。我们还假设，鱼油和双水杨酸的组合与单独使用鱼油相比， 将更有效地增加ω-3 PUFA的循环促消退介质， 在更大程度上比单独鱼油的炎症标志物。脂肪组织中omega-3 PUFA的脂质组学 人类受试者的研究不足，而在糖尿病和DPN受试者中根本没有。有限 在服用鱼油的正常人受试者中进行的研究表明， ω-3多不饱和脂肪酸的循环水平和这种可变性可能会对他们的代谢命运的影响。 所提出的研究将解决这一局限性，并指导我们选择最有效和安全的 用于将ω-3指数增加至治疗水平的鱼油和双水杨酸酯的组合剂量，以及 最大化促分解脂质介质的产生。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 鱼油和双水杨酸的安全特性使它们成为长期临床使用的有吸引力的选择。

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.