Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy: Is the source important?

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In 2015, 9.4% of the United States population had diabetes and statistically about 50% of these patients will or already have developed diabetic peripheral neuropathy (DPN). This problem is even more critical in the veteran health care population with nearly 25% of veterans having diabetes, primarily type 2. In veterans diabetes is the leading cause of blindness, end-stage renal disease and non-trauma related amputations. The only treatment for DPN is glycemic control, which is ineffective in subjects with type 2 diabetes. Thus, there is a critical need of a treatment for DPN. Our studies have demonstrated that treating diabetic rodents with DPN with omega-3 polyunsaturated fatty acids (PUFA) derived from menhaden (fish) oil initiates nerve damage repair and reverses DPN. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the predominate omega-3 PUFA found in fish oil and are the precursors of E and D series resolvins, respectively, which have anti-inflammatory and neuroprotective properties. We have shown that these metabolites alone elicit repair of nerve damage caused by diabetes when administered endogenously in vivo. As we initiate plans to advance omega-3 PUFA to a clinical trial for DPN there remains several questions to be addressed. One common problem with the design of many of the previous clinical trials of omega-3 PUFA primarily for treatment of cardiovascular disease were that they failed to determine the circulating levels of omega-3 PUFA or their metabolites over the course of the study. For most of these studies it was unknown whether dosing was sufficient to make a therapeutic change in the omega-3 index, defined as the sum of EPA and DHA as a percentage of total fatty acids in red blood cells. Another poorly explored question has been what is the best source or composition of omega-3 PUFAs that will provide the most favorable and safe outcome? This is highlighted by the recent REDUCE-IT study that found that a 4 g daily dose of icosapent ethyl (ethyl ester of EPA) to have a statistical benefit on reducing ischemic events in subjects with hypertriglyceridemia. Was the significant outcome achieved in this study due to icosapent ethyl being a more effective source of omega-3 PUFA or use of a higher dose than many previous studies? We have shown that treating type 2 diabetic rats with fish oil that achieved an omega-3 PUFA concentration in serum that was obtained in human subjects treated with 4 g of fish oil per day is an efficacious treatment for DPN. However, is fish oil the best source of omega-3 PUFA for the treatment of DPN or are the ethyl ester derivatives of EPA and/or DHA more efficacious? Ethyl esters of EPA (Vascepa®) or the combination of EPA and DHA (Lovaza®) are pharmaceutical compounds and represent a highly purified and concentrated source of EPA and DHA and void of the less favorable compounds found in fish oil. Studies have shown that EPA and DHA and their metabolites have different molecular targets. Since the etiology of DPN is complex having both vascular and neural pathological pathways it is likely that a combination of EPA and DHA as found in Lovaza® will be needed for an effective treatment of DPN. Besides these pharmaceutical compounds are there other “healthy” alternatives to fish oil for the treatment of DPN? Commercially available algae's that primarily produce EPA or DHA may be another environmental friendly and safe source of omega-3 PUFA. The studies presented in this application will rigorously address the use of these alternative sources of omega-3 PUFA as a treatment for DPN and determine if omega-3 PUFA derived from pharmaceutical compounds i.e. ethyl ester derivatives of EPA or EPA/DHA or from industrial sources such as algae's that solely produce EPA or DHA free of cholesterol may be a better choice than fish oil. The proposed studies will be conducted in rat models of pre-diabetes and type 2 diabetes and will investigate translational endpoints including assessment of motor coordination and balance and function and density of sensory neurons to track the efficacy of omega-3 PUFA on peripheral neuropathy and the results correlated with the omega-3 index and circulating levels of omega-3 PUFA metabolites.