Good glycemic control is the only recognized treatment for diabetic peripheral neuropathy (DPN) but studies have shown that it only slows progression. Therefore, other factors besides hyperglycemia must contribute to DPN, and there is a need for a better understanding of what these factors are in order to discover effective treatments. In the proposed studies we will test the hypothesis that different fatty acid classes have either a negative, neutral or positive effect on DPN. Lipids have been shown to be a major risk factor for diseases but there has been no comprehensive analysis of the effect of different classes of fatty acids on DPN. We will use novel rodent models of type 2 diabetes and manipulate diets so as to increase circulating and tissue levels of monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. Specifically we will examine the potential negative, neutral or positive benefits of dietary enrichment with oleic acid (18:1, MUFA), linoleic acid (18:2, n-6 PUFA), ?-linolenic acid (18:3, n-6 PUFA), ?-linolenic acid (18:3, n-3 PUFA) or eicosapentaenoic acid (20:5, EPA, n-3 PUFA) and docosahexaenoic acid (22:6, DHA, n-3 PUFA) on DPN and neurovascular function. The DPN endpoints will include determination of motor and sensory nerve conduction velocity and changes in the density and function of small sensory nerves in the skin and cornea. The latter endpoints will allow us to examine the effect of fatty acid dietary changes on nerve damage or repair. It is expected that supplementing diets of diabetic rodents with oils enriched in oleic acid (olive oil) or linoleic acid (safflower oil) will have little beneicial effect or may even exacerbate DPN and neurovascular dysfunction. Diets supplemented with ?- linolenic acid (evening primrose oil) or ?-linolenic acid (flaxseed oil) are expected to be beneficial but to a lesser extent than diets supplemented with EPA and DHA, to be derived from menhaden (fish) oil. We propose that increasing dietary levels of n-3 PUFA (derived from flaxseed oil or menhaden oil) but not ?- linolenic acid (n-6 PUFA derived from evening primrose oil) will lower the n-6 to n-3 fatty acid ratio, a marker for reduced inflammation. Due to reduced ability in diabetes of conversion of ?-linolenic acid to EPA we predict that increasing dietary levels of EPA and DHA but not ?-linolenic acid will lead to an increased production of resolvins. Resolvins are produced from EPA and DHA by 15-lipoxygenase-1 (15-LOX-1) and have anti-inflammatory and neuroprotective properties. We propose that EPA and DHA treatment of rodents with type 2 diabetes will have the greatest impact on DPN through reducing inflammatory stress, improving neurovascular function and mediating nerve repair. We also propose that treating rodents with salicylsalicylic acid (salsalate) will increase tissue expressio of 15-LOX-1 leading to increased production of resolvins and even greater efficacy toward DPN and neurovascular complications when rodents with type 2 diabetes are treated with the combination of salsalate and menhaden oil. These preclinical studies will provide needed information to justify clinical trials for the treatment of DPN with fish oils and salsalate.

Public Health Relevance

Good glycemic control is not sufficient to manage diabetic peripheral neuropathy (DPN) suggesting other factors contribute to its etiology and with the increasing rate of type 2 diabetes, DPN and other diabetes complications will continue to increase the cost of healthcare and negatively impact the quality of life for patient and family. Thus, there is a need to determine what these other factors are in order to discover an effective treatment for DPN. We will investigate the impact dietary fatty acids have on DPN as well as explore whether n-3 polyunsaturated fatty acids derived from fish oil (eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA)) will slow progression and stimulate repair of peripheral nerves by reducing inflammatory and oxidative stress and increasing the formation of EPA and DHA metabolites; resolvins and neuroprotectin.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jones, Teresa L Z
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University of Iowa
Internal Medicine/Medicine
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Iowa City
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Coppey, Lawrence; Davidson, Eric; Shevalye, Hanna et al. (2018) Effect of dietary oils on peripheral neuropathy-related endpoints in dietary obese rats. Diabetes Metab Syndr Obes 11:117-127
Davidson, Eric P; Coppey, Lawrence J; Shevalye, Hanna et al. (2018) Effect of Dietary Content of Menhaden Oil with or without Salsalate on Neuropathic Endpoints in High-Fat-Fed/Low-Dose Streptozotocin-Treated Sprague Dawley Rats. J Diabetes Res 2018:2967127
Yorek, Mark A (2018) The Potential Role of Fatty Acids in Treating Diabetic Neuropathy. Curr Diab Rep 18:86
Coppey, Lawrence J; Shevalye, Hanna; Obrosov, Alexander et al. (2018) Determination of peripheral neuropathy in high-fat diet fed low-dose streptozotocin-treated female C57Bl/6J mice and Sprague-Dawley rats. J Diabetes Investig 9:1033-1040
Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna et al. (2017) Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, ?-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints. Neuropharmacology 116:122-131
Obrosov, Alexander; Coppey, Lawrence J; Shevalye, Hanna et al. (2017) Effect of Fish Oil vs. Resolvin D1, E1, Methyl Esters of Resolvins D1 or D2 on Diabetic Peripheral Neuropathy. J Neurol Neurophysiol 8:
Obrosov, Alexander; Shevalye, Hanna; Coppey, Lawrence J et al. (2017) Effect of tempol on peripheral neuropathy in diet-induced obese and high-fat fed/low-dose streptozotocin-treated C57Bl6/J mice. Free Radic Res 51:360-367
Qi, Weier; Keenan, Hillary A; Li, Qian et al. (2017) Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 23:753-762
Davidson, Eric P; Coppey, Lawrence J; Shevalye, Hanna et al. (2017) Impaired Corneal Sensation and Nerve Loss in a Type 2 Rat Model of Chronic Diabetes Is Reversible With Combination Therapy of Menhaden Oil, ?-Lipoic Acid, and Enalapril. Cornea 36:725-731
Yorek, Matthew S; Davidson, Eric P; Poolman, Pieter et al. (2016) Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy. Invest Ophthalmol Vis Sci 57:2412-9

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