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

摘要 2型糖尿病（T2 D）困扰着美国近3000万人，其中至少50%患有神经系统疾病。 包括糖尿病神经病变（DN）的并发症。T2 D的代谢变化产生大量的 周围神经损伤，通常表现为使人衰弱的麻木和神经性疼痛。进展 的神经损伤往往会导致感觉丧失，从而影响患者执行日常任务的能力。 同时也增加了严重受伤的风险。目前尚无有效的DN治疗方法 对于患者来说，他们必须依赖于症状管理选项，这些选项的效果甚微， 副作用严重。对DN新机制的基础研究是迫切需要的， 确定有效的治疗方法。最近的临床研究确定了DN与糖尿病之间前所未有的关联， 糖尿病血脂异常。然而，在了解这些机制方面存在着巨大的差距， 血脂异常调节DN。ω-6多不饱和脂肪酸（PUFA）的氧化代谢物已经被 显示在急性和炎性疼痛状况中通过直接激活 TRPV 1和TRPA 1。然而，没有研究评估其在DN中的作用。我们的中心假设是T2 D- 相关的神经性疼痛是由于ω-6PUFA氧化成神经活性代谢物。测试 假设，我们将：（1）确定T2 D对omega-6 PUFA诱导的激活或致敏的影响 的外周传入神经元，和（2）确定突出的氧化脂质种类，有助于 T2 D中外周传入神经元的激活/敏化。这一建议将使人们对这一作用有新的认识， 并将测试异常omega-6 PUFA氧化与糖尿病肾病之间的因果关系， T2 D患者外周传入神经元功能障碍。这些研究可能产生一种新的机制， 血脂异常改变外周传入神经元功能，产生神经性疼痛，还包括 确定有效治疗DN的新靶点。

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.