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，可能会影响多达50%的 患者，严重增加疼痛和截肢风险，降低体力 功能，增加日常生活负担，生活质量下降，医疗保健费用增加，以及 死亡风险。尽管强化血糖控制被证明可以延缓糖尿病的发生和发展 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 适用于绝大多数2型糖尿病(T2D)患者。尽管不断地进行研究 逆转人类DPN的疾病修正疗法仍然不可用。我们实验室的工作已经 提供了证据表明在鱼油中发现的omega-3多不饱和脂肪酸(PUFA) 联合应用水杨酸盐可能是治疗DPN的有效方法。我们的临床前研究表明，鱼油 水杨酸可延缓DPN的进展，启动神经损伤修复，逆转DPN。我们 还证明了二十碳五烯酸(EPA)的代谢物E和D系列拆分蛋白 和二十二碳六烯酸(DHA)分别逆转DPN的程度与鱼油相似。这些 数据为将鱼油-水杨酸盐联合应用于DPN临床试验提供了理论依据。这个 本申请中提出的研究是这一努力的第一步。将参与者与T2D和 我们将初步确定最有效的鱼油剂量，这将增加omega-3指数 (定义为EPA和DHA之和，占红细胞中总脂肪酸的百分比)到至少 8%-12%被认为是有疗效的。接下来，我们将结合鱼油和盐酸盐来检测它们的 对EPA和DHA衍生的前拆分代谢物产生的影响。我们假设 鱼油以浓度依赖的方式将omega-3指数增加到治疗水平 独立于Salsalate的。我们还假设，与单独使用鱼油相比，将鱼油和水杨酸盐结合在一起 将更有效地增加循环中的omega-3多不饱和脂肪酸的促分解介质，并减少 炎症的标志物比单独使用鱼油的程度更大。Omega-3多不饱和脂肪酸的脂类组学研究 人类受试者的研究不足，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身上进行的研究表明，在 循环中的omega-3多不饱和脂肪酸水平和这种变异性可能会对它们的代谢命运产生影响。 建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 鱼油和水杨酸盐组合剂量将omega-3指数提高到治疗水平和 最大限度地产生有利于分解的脂质介体。这将导致一种疾病修饰的设计 DPN试验，有可能改善所有糖尿病患者的生活质量。最优秀的 鱼油和水杨酸盐的安全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.