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 choic...