Role of Oxidized Omega-6 Fatty Acid Metabolites in Diabetic Neuropathy

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ABSTRACT Type 2 diabetes (T2D) afflicts nearly 30 million individuals in the US, with at least 50% suffering from neurological complications that comprise diabetic neuropathy (DN). The metabolic changes in T2D produce substantial peripheral nerve damage that manifests commonly as debilitating numbness and neuropathic pain. Progression of the nerve damage often leads to loss of sensation that can compromise patients’ ability to execute daily tasks and care for themselves, while also increasing risk of severe injury. No effective treatments for DN are available for patients, who instead must rely on symptom management options that are marginally effective and have burdensome side effect profiles. Fundamental research into novel mechanisms of DN is critically needed to help identify effective treatments. Recent clinical studies identified an unprecedented association between DN and diabetic dyslipidemia. However, there are substantial gaps in knowledge regarding the mechanisms by which dyslipidemia regulates DN. Oxidized metabolites of omega-6 polyunsaturated fatty acids (PUFAs) have been shown to activate and/or sensitize nociceptors in acute and inflammatory pain conditions via direct activation of TRPV1 and TRPA1. However, no studies have evaluated their role in DN. Our central hypothesis is that T2D- associated neuropathic pain is due to oxidation of omega-6 PUFAs into neuronally-active metabolites. To test the hypothesis, we will: (1) determine the effects of T2D on omega-6 PUFA-induced activation or sensitization of peripheral afferent neurons, and (2) identify prominent oxidized lipid species that contribute to activation/sensitization of peripheral afferent neurons in T2D. This proposal will provide new insight into the role of oxidized lipids in DN and will test for a causative link between aberrant omega-6 PUFA oxidation and peripheral afferent neuron dysfunction in T2D. These studies may yield a novel mechanism of how diabetic dyslipidemia alters peripheral afferent neuron function to produce neuropathic pain, which also includes identification of new targets for an effective treatment of DN.