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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
100
Oral capsules, 2 grams or 4 grams per day.
Oral tablets, 1.5 gram or 3.0 gram per day.
University of Iowa
Iowa City, Iowa, United States
Oregon Health Science University
Portland, Oregon, United States
Change from baseline of omega-3 index at 16 and 24 weeks
The omega-3 index is defined as defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells. Red blood cells will be isolated by centrifugation and subsequently analyzed for fatty acid composition following folch extraction of the lipids, derivatization and analysis of the fatty acid profile by gas liquid chromatography. These studies will be done in Dr. Yorek's laboratory.
Time frame: At baseline, 16 weeks and 24 weeks.
Change in baseline of serum levels of resolvin D1, resolvin E1 and neuroprotectin D1, omega-3 polyunsaturated fatty acid metabolites, at 16 and 32 weeks.
Anti-inflammatory mediators, resolvin D1, resolvin E1 and neuroprotectin D1 will be determined using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and authentic standards. Blood will be collected in EDTA/butylated hydroxytoluene/reduced glutathione (EDTA/BHT/GSH) to stabilize lipid mediators by minimizing peroxidation allowing for safe storage at -80C. They will then be analyzed in batches. Results will be reported as pg/ml serum.
Time frame: At baseline, 16 weeks and 24 weeks.
Changes from baseline of serum levels of C reactive protein at 16 and 24 weeks.
A commercial ELISA kit will be used for analysis of C reactive protein in the laboratory of Dr. Yorek at the University of Iowa.
Time frame: At baseline, 16 weeks and 24 weeks.
Changes from baseline of serum levels of tumor necrosis factor α at 16 and 24 weeks.
A commercial ELISA kit will be used for analysis of C tumor necrosis factor α in the laboratory of Dr. Yorek at the University of Iowa.
Time frame: At baseline, 16 weeks and 24 weeks.
Changes from baseline of serum levels of interleukin 6 at 16 and 24 weeks.
A commercial ELISA kit will be used for analysis of analyzed interleukins 6 in the laboratory of Dr. Yorek at the University of Iowa.
Time frame: At baseline, 16 weeks and 24 weeks.
Changes from baseline of serum levels of interleukin 10 at 16 and 24 weeks.
A commercial ELISA kit will be used for analysis of protein interleukins 10 in the laboratory of Dr. Yorek at the University of Iowa.
Time frame: At baseline, 16 weeks and 24 weeks.
Change from baseline in the ratio of omega-6 and omega-3 fatty acids in serum at 16 and 24 weeks
Serum will be folch extracted and fatty acid composition determined following derivatization and analysis by gas-liquid chromatography.
Time frame: At baseline, 16 weeks and 24 weeks.
Change from baseline in diabetic peripheral neuropathy symptoms score after 24 weeks using the Michigan Neuropathy Screening Instrument.
Complete the Michigan Neuropathy Screening Instrument questionnaire. The first part of the screening instrument, the history questionnaire, consists of 15 self-administered "yes or no" questions on foot sensation including pain, numbness and temperature sensitivity. A higher score (out of a maximum of 13 points) indicates more neuropathic symptoms. The minimum score is 1 and maximum score 13.
Time frame: At baseline and 24 weeks.
Change from baseline of vibration perception after 24 weeks.
Vibration perception threshold (a marker of DPN) will be tested using a 128 Hz tuning fork placed over the dorsum of the great toe on the boney prominence of the distal interphalangeal joint of both feet and scored as either present/reduced/absent.
Time frame: At baseline and 24 weeks.
Change from baseline of ankle reflex after 24 weeks.
Ankle reflex (a marker of DPN) will be tested bilaterally and scored as present/present with reinforcement/absent.
Time frame: At baseline and 24 weeks.
Pin prick evaluation
This determination is part of the Utah early neuropathy scale. Pin sensation is tested by determining the sensation of a sharp pin along six points from the great toe to the knee. The subject's eyes are closed and they are asked if they feel any sharpness. Scoring is 0 for normal sensation, 1 for reduced sensation and 2 for absent sensation. The higher the score the worse the neuropathy.
Time frame: At baseline and 24 weeks
Change from baseline in fasting blood glucose after 16 and 24 weeks.
Blood glucose will be determined using an Accu Chek blood glucose monitor.
Time frame: At baseline, 16 weeks, and 24 weeks.
Change from baseline in fasting insulin levels after 16 and 24.
Determination will be done by the hospital pathology laboratory.
Time frame: At baseline, 16 weeks, and 24 weeks.
Change from baseline in hemoglobin A1C after 16 and 24 weeks.
Determination will be done by the hospital pathology laboratory.
Time frame: At baseline, 16 weeks and 24 weeks.
Change from baseline in fasting blood lipids (triglycerides and low- and high-density cholesterol) after 16 and 24 weeks.
Determination will be done by the hospital pathology laboratory.
Time frame: At baseline, 16 weeks and 24 weeks.
Change from baseline in urine microalbuminuria levels after 16 and 24 weeks.
Determination will be done by the hospital pathology laboratory.
Time frame: At baseline, 16 weeks and 24 weeks.
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