Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting about 50% of patients with diabetes and leading to severe morbidity, poor quality of life, high mortality, and high health care costs. Due to the complex structure and anatomy of the peripheral nervous system, DPN presents with a very broad spectrum of clinical symptoms and deficits, including severe pain, sensory deficits, foot ulcers and amputations. Presently there is no treatment for DPN and even with good blood glucose control DPN develops especially in patients with type 2 diabetes. There is a need to identify effective interventions for DPN. Preclinical studies have provided evidence that the combination of fish oil and salsalate is an effective treatment of DPN. The human subject study to be performed will examine the effect of fish oil with and without salsalate on the blood lipid profile and circulating metabolites of omega-3 polyunsaturated fatty acids (PUFA). Fish oil is an excellent source for the nutrition dependent omega-3 PUFA, primarily eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). These fatty acids are the source of anti-inflammatory metabolites known as resolvin, neuroprotectin and maresin. Preclinical studies have also demonstrated that the metabolites of EPA and DHA are neuroprotective. Furthermore, when fish oil is combined with salsalate the production of these metabolites is increased in vivo. Thus, the investigators hypothesize that fish oil and salsalate will be an effective therapy of DPN. However, prior to doing a formal study of the effect of fish oil + salsalate on DPN there is a need to learn more about what concentration combination will provide the most efficacious effect on the omega-3 index (defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells) and that will safely increase the production of the anti-inflammatory metabolites. These studies will be performed at two sites the University of Iowa (Dr. Yorek) and University of Michigan (Dr. Pop-Busui) by treating human subjects with type 2 diabetes and DPN with either 2g or 4g of fish oil per day (capsules) for 4 months and then adding salsalate 1.5 g or 3g per day (tablets) to the fish oil treatments for an additional 2 months. At baseline and after treatment with fish oil alone and after treatment with the combination of fish oil and salsalate the omega-3 index and levels of circulating omega-3 PUFA metabolites will be determined as primary endpoints. Secondary endpoints will include determination of circulatory inflammatory markers and non-invasive measurements for DPN. The risks to subjects are minimal and are very reasonable in relation to the importance of the knowledge to be gained.

The main objective of the investigators studies is to find a safe and effective disease modifying treatment for DPN by translating their preclinical findings (introduced above) to human DPN. However, in an initial step, the investigators' immediate goal is to determine the most effective dosing combination that will raise the omega-3 index to 8-12 % (postulated to be required for a therapeutic effect) and leading to a maximum increase in circulating levels of omega-3 PUFA metabolites. The overall hypothesis is that a tailored supplementation with fish oil will lead to a therapeutic level in the omega-3 index and combining fish oil and salsalate vs. fish oil alone will safely increase the circulating levels of pro-resolving mediators of omega-3 PUFA and reduce markers of inflammation. The investigators will test this hypothesis in a dose finding clinical trial in subjects with type 2 diabetes with DPN. The Specific Aims are:

Specific Aim 1: Determine the optimal dose of fish oil needed to safely increase the omega-3 index to potentially therapeutic levels in subjects with type 2 diabetes and DPN.

Based on the investigator's preclinical studies, they hypothesize that an omega-3 index of 8 - 12% will be needed for effectiveness in human DPN.

Specific Aim 2: Determine the optimal fish oil and salsalate combination on the profile and concentration of circulating omega-3 PUFA metabolites and changes in inflammatory markers in participants with type 2 diabetes and DPN.

The investigators will utilize state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the change in the circulating lipidomic profile of omega-3 PUFA, and antibody-based assays to measure circulating inflammatory markers: C reactive protein, tumor necrosis factor alpha; and interleukins 6 and 10 in response to above combination in human subjects with type 2 diabetes and DPN.

Completing these aims will establish the optimal dose of fish oil-salsalate combination needed to raise the omega-3 index to potentially therapeutic levels in patients with type 2 diabetes and DPN, and their effect on the formation of the pro-resolving metabolites of omega-3 PUFA in circulation in these subjects.

The investigators proposed research will have immediate significant impact by generating the knowledge needed for the design of a phase 2/3 trial in human DPN to determine whether fish oil and salsalate in combination is an effective disease modifying therapy for DPN. The safety profile of fish oil and salsalate are excellent making them an ideal choice for chronic treatment of DPN.

Inclusion Criteria:

1. T2D according to American Diabetes Association (ADA) criteria (38).
2. Age ≥ 18 yr.
3. HbA1c < 9.5%.
4. Presence of DPN based on Michigan Neuropathy Screening Instrument (combined questionnaire and a clinical examination of the response to vibration perception examination using a 128 Hz tuning fork and ankle reflexes), a validated, sensitive, and specific instrument for the diagnosis of DPN as reported (39,40). Pin prick sensation will be performed (as measures of small-fiber neuropathy) for DPN confirmation (41-43).
5. Be willing and capable of providing a written consent form and willing and able to cooperate with the medical procedures for the study duration.
6. Women of childbearing potential must be willing to use appropriate contraception during the entire trial.

Exclusion Criteria:

1. History of any other causes of neuropathy (e.g. other neurological disorders, medications-induced, occupational history, active hepatitis C infection, exposure to toxins).
2. History of persistent macroalbuminuria [random urine microalbumin creatinine ratio (ACR) up to 300 mg/gm]is acceptable if calculated GFR is >60 (16).
3. Serum creatinine >1.4 for women and >1.5 for men or eGFR <60 [calculated using the CKD-EPI equation].
4. Use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants, probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents; Participants must agree to not use high-dose aspirin during the course of the study. Daily low-dose aspirin treatment (not more than 81 mg per day) may be continued if currently prescribed.
5. Uncontrolled hypertension
6. Triglyceride > 400 mg/100ml.
7. History of previous organ transplantation (kidney, pancreas, liver, lung or cardiac transplantation).
8. History of drug or alcohol abuse within 5 years, or current weekly alcohol consumption >10 units/week.
9. Pregnancy or breast feeding or desire to become pregnant in the next 12 months
10. Requiring long-term glucocorticoid therapy or chronic immunosuppressive therapy including daily use of inhaled glucocorticoids. Periodic or intermittent use of inhaled glucocorticoids (less than daily) is allowable.
11. Participation in an experimental medication trial within 3 months of starting the study.
12. Current therapy for malignant disease other than basal cell or squamous cell skin cancer.
13. History of gastrointestinal bleeding or active gastric ulcer;
14. Screening laboratory abnormalities including AST (SGOT) and or ALT (SGPT) > 2.5 x the upper limit of normal (ULN), total bilirubin > 1.5 x ULN, platelets < 100,000;
15. History of taking fish oil supplements in the 6 months prior to the screening visit.
16. History of fish or shellfish allergy.
17. Presence of any condition that in the opinion of the investigators would make it unlikely for the participant to complete study.
18. Known hypersensitivity to salsalate or inactive ingredients. Patients who have experienced asthma, hives, or other allergic-type reactions to aspirin or other NSAIDs are excluded from participation.
19. Use of lithium.
20. Absent one or both great toes.
21. Untreated hypothyroidism.
22. Severe peripheral vascular, or cardiac disorders including pre-existing atrial fibrillation, pulmonary, or any other disorder affecting blood or tissue oxygenation.

The research to be done will not generate any usable resources. We will publish our methodology for all analyses in detail in manuscripts we submit for publication we will also make this information available through our websites. We will also make available on our websites de-identified data pertaining to individual results of the omega-3 index and omega-3 polyunsaturated fatty acid metabolites formed per treatment condition. Other original de-identified data will also be made available upon request.