Linking Nerve Bioenergetics with Metabolomics: New Insights into Diabetic Neuroapthy

将神经生物能量学与代谢组学联系起来：对糖尿病神经病变的新见解

• 批准号: 9769901
• 负责人: Eva Lucille Feldman
• 金额: $ 27.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769901
• 关键词: Address; Affect; Age; Amino Acids; Bioenergetics; Biological; Biological Markers; Body Weight decreased; Carbohydrates; Chronic; Clinic; Clinical Research; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Intervention; Disease; Early Diagnosis; Early Intervention; Economic Burden; Enrollment; Epidemic; Functional disorder; Funding; Glucose; Glycolysis; Goals; High Fat Diet; Human; Hyperglycemia; Intervention; Investigation; Knowledge; Limb structure; Link; Lipids; Mass Spectrum Analysis; Measures; Metabolic; Metabolic syndrome; Metabolism; Michigan; Mitochondria; Modeling; Mus; Nerve; Nerve Tissue; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Nutrient; Obesity; Onset of illness; Optics; Outcome; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Nerves; Peripheral Nervous System Diseases; Phenotype; Plasma; Play; Prediabetes syndrome; Production; Quality of life; Regulation; Research; Research Design; Role; Signs and Symptoms; Spinal Ganglia; Technology; Testing; Tissues; United States National Institutes of Health; Universities; Weight maintenance regimen; base; blood glucose regulation; db/db mouse; diabetic; diabetic patient; exercise intervention; fatty acid metabolism; fatty acid oxidation; glucose metabolism; human subject; improved; insight; man; meetings; metabolic phenotype; metabolomics; mitochondrial metabolism; mouse model; novel therapeutic intervention; sciatic nerve; sural nerve

ABSTRACT Diabetes is associated with altered carbohydrate, amino acid, and fatty acid metabolism, contributing to diabetic complications, including diabetic peripheral neuropathy (PN). Diabetic PN affects ~60% of diabetic patients and is characterized by progressive loss of peripheral nerves in a stocking and glove pattern (extremities affected first), with pain and eventual loss of sensation. Despite extensive research over recent decades, the pathogenesis of DN remains unclear, and there is no treatment beyond traditional glucose control, which hardly affects PN development and progression in type 2 diabetes (T2D). Therefore, there is a critical need to determine the specific metabolic mechanisms contributing to the onset and progression of DN in order to identify mechanism-based intervention strategies. Our long-term goal is to meet this need and develop much-needed therapies that impact PN before the onset of disease in order to significantly improve quality of life of diabetic patients. In the current proposal, our objective is to leverage human subjects enrolled in an NIH-funded clinical study at the Investigational Weight Management Clinic (IWMC) at the University of Michigan and a mouse model of high fat diet (HFD)-induced obesity, prediabetes, and PN to identify the mechanisms that contribute to PN pathogenesis. We hypothesize that distinct metabolic alterations occur in obesity, prediabetes, and T2D which induce metabolic reprogramming within the peripheral nerve, altering fuel utilization and ultimately leading to tissue dysfunction. We will test this hypothesis in two aims. First, we will use sensitive and specific mass spectrometry-based metabolomic analysis on plasma from obese, prediabetic human subjects with PN in the IWMC study and from mouse models with PN. Mice will be fed standard diet (SD) or HFD from 5-16 wk of age. We will compare the metabolomic profiles between humans and mice with PN, with the goal of identifying both common and distinct signatures that associate with PN. This cross-species approach will allow us to discover pathogenic metabolomic signatures to act as biomarker(s) of PN in man and mouse, and to identify candidate pathways and molecules whose regulation play crucial roles in the pathogenesis of PN. Second, we will measure changes in mitochondrial function and fuel substrate utilization in peripheral nerve from the mice with PN before and after weight loss. We will use five groups of mice: mice fed SD or HFD from 5-16 wk of age, mice fed a SD or HFD from 5-24 wk, and mice fed a HFD from 5-16 wk then switched to SD from 16-24 wk [HFD- dietary reversal (HFD-DR)]. Notably, HFD-DR mice show significant regression of all PN parameters at 24 wk. These studies will link nerve-specific bioenergetic abnormalities and PN phenotypes to identify candidate bioenergetic pathways whose regulation play crucial roles in the pathogenesis of PN. Together, the proposed studies using obese, prediabetic patients and mice with PN will increase our understanding of how the peripheral nerve adapts to chronic and specific changes in substrate availability beyond excess glucose.

摘要 糖尿病与碳水化合物、氨基酸和脂肪酸代谢的改变有关， 糖尿病并发症，包括糖尿病周围神经病变（PN）。糖尿病PN影响约60%的糖尿病患者 患者，其特征是在长袜和手套模式中进行性丧失外周神经 （四肢首先受影响），伴有疼痛和最终感觉丧失。尽管最近进行了广泛的研究， 几十年来，DN的发病机制仍不清楚，除了传统的葡萄糖治疗外， 对照，其几乎不影响2型糖尿病（T2 D）中PN的发展和进展。因此有 迫切需要确定导致DN发生和进展的特定代谢机制 以确定基于机制的干预策略。 我们的长期目标是满足这一需求，并开发出急需的治疗方法，在 以显著改善糖尿病患者的生活质量。在目前的建议中， 目的是利用在NIH资助的临床研究中招募的人类受试者， 管理诊所（IWMC）在密歇根大学和高脂肪饮食（HFD）诱导的小鼠模型 肥胖、前驱糖尿病和PN，以确定导致PN发病的机制。我们假设 在肥胖、糖尿病前期和T2 D中发生不同的代谢改变， 在外周神经内重新编程，改变燃料利用并最终导致组织功能障碍。 我们将从两个方面来检验这一假设。首先，我们将使用灵敏和特异的质谱法 对IWMC研究中患有PN的肥胖、糖尿病前期人类受试者和 PN小鼠模型。小鼠从5-16周龄开始喂食标准饮食（SD）或HFD。我们将比较 人和PN小鼠之间的代谢组学特征，目的是识别共同和不同的代谢组学特征。 与PN相关的签名。这种跨物种的方法将使我们能够发现致病的 代谢组学特征作为人和小鼠中PN的生物标志物，并识别候选途径 以及其调节在PN发病机制中起关键作用的分子。第二，我们将衡量 PN小鼠周围神经线粒体功能和燃料底物利用的变化 减肥前后我们将使用五组小鼠：从5-16周龄喂食SD或HFD的小鼠， 从5-24周喂食SD或HFD，从5-16周喂食HFD，然后从16-24周转换为SD [HFD- 饮食逆转（HFD-DR）]。值得注意的是，HFD-DR小鼠在24周时显示所有PN参数的显著回归。 这些研究将神经特异性生物能量异常和PN表型联系起来，以确定候选的 生物能量途径，其调节在PN的发病机制中起关键作用。在一起，拟议的 使用肥胖、糖尿病前期患者和PN小鼠的研究将增加我们对 外周神经适应除过量葡萄糖之外的底物可用性的慢性和特异性变化。