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Impact of insulin on lactate metabolism

胰岛素对乳酸代谢的影响

基本信息

批准号：
10901004
负责人：
Won Dong Lee
金额：
$ 0.25万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901004
关键词：
Adipose tissue Affect Animals Biochemical Blood Circulation Carbon Carbon Dioxide Catabolism Citric Acid Cycle Communication Consumption Coupled Critical Illness Data Diabetes Mellitus Eating Energy Metabolism Epidemic Fasting Fatty Acids Fatty acid glycerol esters Functional disorder Future GLUT 4 protein Genetically Engineered Mouse Gluconeogenesis Glucose Glycolysis Goals Growth Health Homeostasis Hormones Indirect Calorimetry Individual Infusion procedures Insulin Insulin Receptor Investigation Isotope Labeling Isotopes Knockout Mice Knowledge Label Lead Leadership Lipolysis Measures Medical Metabolic Metabolic syndrome Metabolism Modeling Mus Muscle Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Organ Oxygen Consumption Pathogenesis Patients Persons Phosphorylation Physiological Plasma Positioning Attribute Postprandial Period Production Pyruvate Dehydrogenase E1 Regulation Research Role Scientist Site Testing Tissues Tracer Training Programs Work blood glucose regulation design experimental study feeding glucose uptake glycemic control hepatic gluconeogenesis in vivo insulin signaling lipid metabolism metabolic abnormality assessment metabolomics novel oxidation pyruvate dehydrogenase respiratory response skills

项目摘要

Project Summary/Abstract The goal of this research is to explore the hypothesis that insulin promotes lactate burning, and to lay the groundwork for future investigation of the importance of such regulation to glucose homeostasis and diabetes. Actively transformed to each other by glycolysis and gluconeogenesis, glucose and lactate metabolism are tightly connected. Imbalances between lactate production and consumption lead to altered lactate concentrations, which can affect glycemia. Moreover, lactate accumulation (hyperlactatemia) is one of the most frequently encountered metabolic alterations in critically ill patients. Understanding the control of lactate production and utilization is therefore medically relevant, especially for more completely elucidating the pathophysiology of type 2 diabetes. Unlike for glucose, however, the mechanisms regulating lactate homeostasis are largely unknown. Here I will investigate the systemic and tissue-specific impact of insulin on lactate metabolism, test the hypothesis that insulin promotes lactate oxidation via TCA cycle, and explore the underlying biochemical mechanisms. To this end, Aim 1 will investigate the impact of insulin on whole-body and organ-specific TCA cycle activity. To measure the effect of insulin on whole body energy metabolism, insulin will be given to mice after short fasting, and oxygen consumption and carbon dioxide production will be measured by indirect calorimetry. To understand the impact of insulin on organ-specific TCA metabolism, TCA flux in individual organs will be quantified, using a novel dynamic isotope tracing approach coupled to LC-MS and flux modeling. Aim 2 will explore the mechanisms by which insulin changes tissue TCA metabolism. In particular, I will assess whether increased lactate contribution to TCA cycle depends on (i) insulin’s induction of glucose uptake, (ii) insulin’s inhibition of adipose lipolysis and associated decrease in circulating free fatty acids as alternative fuels, or (iii) insulin’s direct stimulation of lactate burning, likely via regulation of pyruvate dehydrogenase (PDH) activity. These alternatives will be rigorously examined using genetically engineered mouse models and in vivo metabolic flux analysis. Completion of these studies is poised to substantially advance understanding of mammalian metabolism, by illuminating a potentially major regulatory mechanism of likely importance to the pathogenesis of metabolic syndrome. The applicant brings unique pre-existing strengths in metabolic flux analysis at the cellular and subcellular level, but has not previously worked in vivo. Accordingly, the training program is designed to build physiological knowledge, animal handling skills, and organismal-level quantitative modeling capacity. Acquisition of this technical knowledge, combined with further growth in leadership abilities, will position the applicant to eventually become a pioneering independent scientist, studying metabolism quantitatively across spatial scales, from subcellular to organismal.

项目摘要/摘要这项研究的目的是探索胰岛素促进乳酸燃烧的假设，并奠定为未来研究这种调节对血糖稳态和糖尿病的重要性奠定基础。通过糖酵解和糖异生相互转化，葡萄糖和乳酸代谢紧密连接在一起。乳酸生产和消费之间的不平衡导致乳酸浓度的变化，这会影响血糖。此外，乳酸蓄积(高乳酸血症)是最常见的在危重病人中遇到代谢改变。了解乳酸盐生产和生产的控制因此，利用它在医学上是有意义的，尤其是对于更全面地阐明类风湿关节炎的病理生理学。 2糖尿病。然而，与葡萄糖不同的是，调节乳酸稳态的机制在很大程度上是未知的。在这里，我将研究胰岛素对乳酸代谢的系统和组织特异性影响，检验这一假设认为胰岛素通过TCA循环促进乳酸氧化，并探讨其潜在的生化机制。至为此，目标1将研究胰岛素对全身和器官特异性TCA循环活动的影响。至测量胰岛素对全身能量代谢的影响，小鼠短期禁食后给予胰岛素，氧气消耗和二氧化碳产生将通过间接量热法测量。要理解胰岛素对器官特异性TCA代谢的影响，单个器官中的TCA通量将被量化，使用液质联用和通量模拟相结合的动态同位素示踪新方法目标2将探索这些机制胰岛素通过这种方式改变组织中的TCA代谢。特别是，我会评估乳酸盐增加是否对TCA循环的贡献取决于(I)胰岛素诱导葡萄糖摄取，(Ii)胰岛素抑制脂肪作为替代燃料的脂肪分解和循环中游离脂肪酸的相关减少，或(Iii)胰岛素的直接刺激乳酸燃烧，可能是通过调节丙酮酸脱氢酶(PDH)活性。这些替代方案将使用基因工程小鼠模型和体内代谢流量分析进行严格检查。这些研究的完成将极大地促进对哺乳动物新陈代谢的了解阐明了一种可能对代谢发病机制具有重要意义的潜在的主要调节机制综合症。申请者在细胞和细胞代谢流量分析方面具有独特的优势亚细胞水平，但以前从未在体内起作用。因此，培训方案旨在建立具备生理学知识、动物操作技能和生物体水平的定量建模能力。采办这些技术知识，再加上领导能力的进一步发展，将使申请者能够最终成为一名开拓性的独立科学家，跨空间尺度定量研究新陈代谢，从亚细胞到生物体。