Omega-3 Fatty Acid Lipidomics in Diabetes Peripheral Neuropathy

• Status: Not yet recruiting
• Trial end date: 2026-01-01
• Target enrollment: 0
• Participant gender: All

Summary

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 4 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.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Iowa
• Collaborator: University of Michigan
• Treatments: Salicylsalicylic acid

Criteria

Inclusion Criteria:

1. T2D according to American Diabetes Association (ADA) criteria.

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. Quantitative sensory testing (QST) to hot and cold sensation evaluations (as measures of small-fiber neuropathy) will be also performed for DPN confirmation.

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.

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. Untreated hypothyroidism.

3. Severe peripheral vascular, cardiac including pre-existing atrial fibrillation, pulmonary, or any other disorder affecting blood or tissue oxygenation.

4. History of persistent macroalbuminuria (microalbuminuria up to 300 mg/24 hours is acceptable if calculated GFR is >60.

5. Serum creatinine >1.4 for women and >1.5 for men or eGFR <50 [calculated using the Modification of Diet in Renal Disease (MDRD) equation].

6. Risk of bleeding disorder known to increase risk of bleeding or on medication for anticoagulation.

7. Repeated use of aspirin other than 81 mg daily.

8. Triglyceride > 400 mg/100ml.

9. History of previous kidney, pancreas, liver, or cardiac transplantation.

10. History of drug or alcohol abuse within 5 years, or current weekly alcohol consumption >10 units/week.

11. Pregnancy or lactation or desire to become pregnant.

12. Requiring long-term glucocorticoid therapy.

13. Participation in an experimental medication trial within 3 months of starting the study.

14. Undergoing therapy for malignant disease.

15. History of gastrointestinal bleeding or active gastric ulcer.

16. History of taking fish oil supplements in the last 6 months.

17. History of fish or shellfish allergy.

18. Presence of any condition that in the opinion of the investigators would make it unlikely for the subject to complete study.

19. Known hypersensitivity to salsalate. Patients who have experienced asthma, hives, or other allergic-type reactions to aspirin or other NSAIDs are excluded from participation.