Painful Versus Insensate Diabetic Neuropathy

项目摘要 糖尿病前期和糖尿病患者发生糖尿病周围神经病变（DPN）的风险升高。 DPN主要影响远端肢体，并与疼痛、感觉丧失、步态异常和 生活质量下降。此次更新将重点关注使用生酮饮食（KD）的饮食干预，以预防 并逆转DPN的症状KD的消耗导致酮体升高，β- 羟基丁酸（bOHB）和乙酰乙酸作为关键介质。由肝脏产生，酮体可用于 直接通过非肝细胞，如神经元，作为葡萄糖的替代燃料源或具有信号传导能力。 DPN中的轴突变性，特别是小纤维，导致表皮神经支配减少， 目前没有临床治疗。感觉轴突的代谢和能量状态导致轴突损失， 添加酮体作为燃料源可能是细胞能量的重要调节剂， 代谢功能疼痛是DPN患者生活质量下降的主要原因， 由于缺乏有效的临床治疗而受到损害。我们的总体假设是酮体改善 DPN通过直接作用于感觉神经元的特征。我们将使用饮食来检验我们的假设。 在糖尿病前期和糖尿病小鼠模型中进行干预，并结合Cre-lox小鼠模型 缺乏利用感觉神经元中的酮体的能力（advCre-SCOT-/-小鼠）来确定是否直接 酮对外周感觉神经元的作用驱动这些有益的作用。目标1将测试酮是否 体直接作用于感觉神经元以刺激DPN中的轴突生长。实验将包括体外 以及KD导致的轴突生长的体内评估，并探索参与KD的细胞信号传导途径。 轴突导向、能量信号通路和线粒体功能。目标2将测试酮体是否 通过清除MGO减轻DPN中的疼痛（机械性异常性疼痛）。实验将包括离体 电生理学以识别在MGO的设置中识别的感觉神经元的响应和放电特性，以及 KD。其他实验将测试KD是否在化疗中具有类似的抗伤害感受作用- 诱导的神经病模型，其中代谢的变化不起作用。这些研究的结果将填补 通过提供关于KD如何改善神经元功能的新信息， 代谢和刺激轴突生长。这些结果将确定可以开发用于疼痛的干预措施 DPN的控制，包括与MGO毒性相关的新机制。

Project Summary Patients with prediabetes and diabetes are at an elevated risk for diabetic peripheral neuropathy (DPN). DPN primarily affects the distal limbs and is associated with pain, loss of sensation, gait abnormalities and reduced quality of life. This renewal will focus on a dietary intervention using a ketogenic diet (KD) to prevent and reverse symptoms of DPN. Consumption of a KD results in elevated ketone bodies, with beta- hydroxybutyrate (bOHB) and acetoacetate as key mediators. Generated by the liver, ketone bodies can be used directly by non-hepatic cells, such as neurons, as an alternative fuel source to glucose or in a signaling capacity. Axon degeneration in DPN, particularly small fibers, leads to reduced epidermal innervation for which there are currently no clinical treatments. The metabolic and energetic status of sensory axons contributes to axon loss, and the addition of ketone bodies as a fuel source could be an important modulator of cellular energy and metabolic function. Pain is a major contributor to decreased quality of life in patients with DPN, which is compromised by a lack of effective clinical treatments. Our overall hypothesis is that ketone bodies improve features of DPN through actions directly on sensory neurons. We will test our hypothesis using dietary interventions in mouse models of prediabetes and diabetes, as well as incorporate a Cre-lox mouse model lacking the ability to utilize ketone bodies in sensory neurons (advCre-SCOT-/- mice) to determine whether direct effects of ketones on peripheral sensory neurons drive these beneficial effects. Aim 1 will test whether ketone bodies act directly on sensory neurons to stimulate axon growth in DPN. Experiments will include both in vitro and in vivo assessment of axon growth as a result of a KD, and explore cellular signaling pathways involved in axon guidance, energy signaling pathways, and mitochondrial function. Aim 2 will test whether ketone bodies reduce pain (mechanical allodynia) in DPN by scavenging MGO. Experiments will incorporate ex vivo electrophysiology to identify response and firing properties of identified sensory neurons in settings of MGO and a KD. Additional experiments will test whether a KD has similar anti-nociceptive action in a chemotherapy- induced neuropathy model where changes in metabolism do not play a role. Results from these studies will fill an important gap in DPN research by providing new information about how a KD can improve neuronal metabolism and stimulate axon growth. These results will identify interventions that could be developed for pain control in DPN, including new mechanisms related to MGO toxicity.