Painful Versus Insensate Diabetic Neuropathy

项目摘要 糖尿病前期和糖尿病患者患糖尿病周围神经病变(DPN)的风险较高。 DPN主要影响四肢远端，与疼痛、感觉丧失、步态异常和 生活质量下降。这次更新将集中在使用生酮饮食(KD)的饮食干预上，以防止 逆转DPN的症状。摄入KD会导致酮体升高，并伴随β- 羟基丁酸酯(BOHB)和乙酰乙酸酯为关键介体。由肝脏生成，酮体可用 直接由非肝细胞，如神经元，作为葡萄糖的替代燃料来源或在信号能力方面。 DPN中的轴突变性，特别是细小的纤维，导致表皮神经支配减少，对此有 目前还没有临床治疗方法。感觉轴突的新陈代谢和能量状态导致轴突丢失， 作为燃料来源的酮体的添加可能是细胞能量的重要调节器和 新陈代谢功能。疼痛是导致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可以改善 DPN通过直接作用于感觉神经元的特征。我们将使用膳食来检验我们的假设 对糖尿病前期和糖尿病小鼠模型的干预，以及纳入Cre-lox小鼠模型 缺乏利用感觉神经元(AdvCre-Scot-/-小鼠)中的酮体来确定是否直接 酮对外周感觉神经元的影响推动了这些有益的影响。目标一号将测试酮 身体直接作用于感觉神经元以刺激DPN内轴突的生长。实验将包括这两种体外实验 并在体内评估作为KD结果的轴突生长，并探索参与的细胞信号通路 轴突引导、能量信号通路和线粒体功能。目标2将测试酮体 通过清除MGO来减轻DPN中的疼痛(机械性超敏)。实验将包括体外实验 电生理学以确定已识别的感觉神经元在MGO和 一个KD。其他实验将测试KD在化疗中是否具有类似的抗伤害性作用- 诱发性神经病模型，代谢改变不起作用。这些研究的结果将填补 通过提供有关KD如何改善神经元的新信息，DPN研究中的一个重要空白 促进新陈代谢，刺激轴突生长。这些结果将确定可以开发的疼痛干预措施 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.