Peripheral neuropathy (PN) affects about 50% of the diabetic population. The symptoms range from pain, numbness, paresthesia and ulceration in the extremities and PN is the major cause of non-traumatic amputations. In 2010 the VA healthcare system spent $206 million on care of veterans that received lower- limb amputations due to diabetes-induced PN. This single statistic illustrates the impact of this disease and the devastating effect it has on the quality of life and functioning of veterans and their families as well as the large cost burden on the VA healthcare system. We now know that PN can develop before the onset of hyperglycemia and can be detected in subjects with pre-diabetes and impaired glucose tolerance. These subjects are often overweight with symptoms of metabolic syndrome. Recent statistics indicate that 72% of all Veterans are overweight or obese placing them at high risk of developing PN and type 2 diabetes. The diagnosis of PN in its early stages is challenging and no treatment is available, besides glycemic control, which is ineffective for type 2 diabetes. With the prevalence of obesity and type 2 diabetes at epidemic levels in both the veteran and general populations there is a critical need for improving the diagnosis of PN and finding a treatment. The goals of this proposal are to investigate both of these important issues. A key to improving treatment of PN like many disorders is early detection. Presently, the clinical diagnosis for PN is subjective with most veterans receiving a diagnosis of PN only after presenting with symptoms and advanced PN. Earlier diagnosis of PN is needed if new treatments aimed at preserving nerves and stimulating regeneration is to be successful. Recently, loss of sub-epithelial corneal nerves has been promoted as being a surrogate marker of PN. However, utilizing corneal confocal microscopy to evaluate loss of corneal nerves as a routine method to detect PN would be challenging. Thus, we have developed an objective test relying on corneal sensitivity as a simple screening method for detecting PN. The method employs the use of a hyperosmolar eye drop to activate transient receptor channel-8 receptors in the cornea to cause reflex blinking and squinting if the nerves are intact. Even before the onset of hyperglycemia, i.e. pre-diabetes, damaged peripheral nerves lose sensation, and will have less reflex response to corneal stimulation. Development of a method of early detection of PN that can be performed annually during a routine clinical primary care visit or eye examination would improve the standard of care for veterans with diabetes. In this application we will also extend our examination of a safe and cost effective treatment to slow progression and reverse nerve damage caused by PN, thereby providing veterans a solution for this devastating problem. We first introduced fish oil as a treatment of PN in VA supported pre-clinical studies in the last funding period and will continue these studies culminating in a feasibility study for treating human subjects with type 2 diabetes and neuropathy. Our previous studies suggest that long-chain omega-3 (n-3) polyunsaturated fatty acids that are commonly found in fish oils, primarily eicosapentaenoic acid and docosahexaenoic acid, may be an effective treatment for PN associated with pre-diabetes and diabetes. Consumption of n-3 polyunsaturated fatty acids found in fish oils is low in the Western diet due to historically increased consumption of n-6 polyunsaturated fatty acids. Numerous clinical studies suggest potential benefits of n-3 polyunsaturated fatty acid consumption on various diseases. Therefore, there is a tremendous interest in increasing the dietary intake of n-3 polyunsaturated fatty acids as a capsule for the general public and for select clinical populations that may benefit the most. Even though the health benefits of n-3 polyunsaturated fatty acids have been widely examined, their role as a potential treatment for diabetes complications, including PN, have not been thoroughly studied. The studies presented in this application will fill this void and will provide rationale to advance to clinical trials n-3 polyunsaturated fatty acids, i.e. fish oils as a treatment for PN.

Public Health Relevance

Peripheral neuropathy (PN) is a major complication of diabetes affecting about 50% of the veteran population. The symptoms range from pain, numbness, paresthesia and ulceration in the extremities it is also the major cause of non-traumatic amputations. Besides pain management the only option physicians have to slow progression of PN is glycemic control but in type 2 diabetes even good glycemic control is ineffective. Presently we do not even have a way to diagnosis PN in its early stages. This proposal has two major goals. The first goal is to validate a novel method for early detection of PN. Recently decrease in corneal nerves in the sub-epithelial layer has been promoted as a surrogate marker for PN. We will determine if corneal sensitivity to a hyperosmotic solution is a valid marker of PN. The second goal is to determine whether fish oil can promote repair and regeneration of corneal nerves when applied topically or through the diet. If successful these studies will provide a proof of concept to advance fish oils to clinical trials for PN.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX000889-06
Application #
9408443
Study Section
Sensory Systems/Communication Disorders (RRD3)
Project Start
2013-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
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Ledolter, Johannes; Kardon, Randy H (2017) Does Testing More Frequently Shorten the Time to Detect Disease Progression? Transl Vis Sci Technol 6:1
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
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; Coppey, Lawrence J; Shevalye, Hanna et al. (2016) Effect of Treatment with Salsalate, Menhaden Oil, Combination of Salsalate and Menhaden Oil, or Resolvin D1 of C57Bl/6J Type 1 Diabetic Mouse on Neuropathic Endpoints. J Nutr Metab 2016:5905891
Yorek, M A (2016) Alternatives to the Streptozotocin-Diabetic Rodent. Int Rev Neurobiol 127:89-112
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
Yorek, Matthew S; Obrosov, Alexander; Lu, Bao et al. (2016) Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice. J Neuropathol Exp Neurol :
Shevalye, Hanna; Yorek, Matthew S; Coppey, Lawrence J et al. (2015) Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on neuropathy in a mouse model of type 2 diabetes. J Neurophysiol 114:199-208
Coppey, Lawrence J; Davidson, Eric P; Obrosov, Alexander et al. (2015) Enriching the diet with menhaden oil improves peripheral neuropathy in streptozotocin-induced type 1 diabetic rats. J Neurophysiol 113:701-8

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