FAT AND CARBOHYDRATE METABOLISM IN SKELETAL MUSCLE

骨骼肌中的脂肪和碳水化合物代谢

• 批准号: 8171635
• 负责人: Craig R Malloy
• 金额: $ 10.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171635
• 关键词: ATP Synthesis Pathway; Age; Animals; Carbohydrate Biochemistry; Citric Acid Cycle; Clinical; Clinical Research Protocols; Communities; Computer Retrieval of Information on Scientific Projects Database; Contrast Media; Control Animal; Defect; Development; Diabetes Mellitus; Diet; Fasting; Fatty acid glycerol esters; Funding; Glucagon; Glucose; Goals; Grant; Hepatic; Human; Image; Institution; Insulin Resistance; Isotopes; Ketones; Kinetics; Lipolysis; Liver; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Organ; Pathway interactions; Patients; Physiology; Population; Production; Rattus; Research; Research Personnel; Resources; Rodent Model; Skeletal Muscle; Source; Spectrum Analysis; United States National Institutes of Health; Urea; Zucker Rats; base; carbohydrate metabolism; fatty acid oxidation; glucose production; hepatic gluconeogenesis; human subject; imaging modality; method development; novel strategies; oxidation; stable isotope; success; technology development; volunteer; ATP Synthesis Pathway; Age; Animals; Carbohydrate Biochemistry; Citric Acid Cycle; Clinical; Clinical Research Protocols; Communities; Computer Retrieval of Information on Scientific Projects Database; Contrast Media; Control Animal; Defect; Development; Diabetes Mellitus; Diet; Fasting; Fatty acid glycerol esters; Funding; Glucagon; Glucose; Goals; Grant; Hepatic; Human; Image; Institution; Insulin Resistance; Isotopes; Ketones; Kinetics; Lipolysis; Liver; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Organ; Pathway interactions; Patients; Physiology; Population; Production; Rattus; Research; Research Personnel; Resources; Rodent Model; Skeletal Muscle; Source; Spectrum Analysis; United States National Institutes of Health; Urea; Zucker Rats; base; carbohydrate metabolism; fatty acid oxidation; glucose production; hepatic gluconeogenesis; human subject; imaging modality; method development; novel strategies; oxidation; stable isotope; success; technology development; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This core research and technology development project has three aims. All are related to the development of new approaches to measuring key fluxes and metabolites important to fat and carbohydrate biochemistry in people. Over the long term, we envision a set of clinical research protocols involving systemic administration of 13C and 2H to determine the kinetics of whole-body glucose production, hepatic fatty acid oxidation, etc., whichare fundamental to understanding the physiology of insulin-resistant states. Simultaneously, organ-specific MR imaging and spectroscopy can be used to probe metabolism in critical organs such as skeletal muscle and liver. Based on our success with stable isotope analysis of metabolism plus our recent progress with magnetization transfer contrast agents (PARACEST agents), this goal can be achieved in experimental animals, and proof-of-concept development will be carried out in human subjects. Specific Aim #1 is to implement and evaluate new metabolic imaging methods in rodent models. Glucose imaging by MRI will be studied in three populations of rats: control animals, hyperthyroid rats, and Zucker fatty rats. By manipulation of nutritional state and glucagon, the concentration and distribution of glucose will be altered in the whole animal. Simultaneous measures of glucose turnover, urea turnover, ketone production, systemic lipolysis and hepatic 13 oxidation will be determined by isotope methods. Specific Aim #2 is to continue development of methods to measure hepatic 13 - oxidation, whole-body lipolysis, gluconeogenesis and hepatic TCA cycle flux in human subjects. The clinical and scientific community wants to be able to routinely measure fatty acid oxidation in the liver. In this Aim of Core 3, methods developed in Core 1 will be extended to patients and volunteers. Hepatic gluconeogenesis and 13 oxidation will be measured in three human populations: fasting, high fat diet, and type 2 diabetes. We have already shown metabolic changes in glucose production pathways in these various metabolic states, some of which are dramatic changes. Finally, specific Aim #3 is to assess intramyocellular fat content and mitochondrial function in skeletal muscle of patients with T2 diabetes. Abnormal intramyocellular fat content, excess hepatic gluconeogenesis, and a widespread defect in mitochondrial function have been postulated among patients with T2D. In calf muscle of fasted control subjects and age matched patients with type 2 diabetes, three measurements will be made: intramyocellular fat content, ATP synthesis rates (by 31p NMR magnetization transfer) and citric acid cycle flux (by 1 H decouple, 13C observe NMR).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这个核心研究与技术开发项目具有三个目标。所有这些都与开发新方法的开发，以测量对脂肪和碳水化合物生物化学重要的关键通量和代谢产物的发展。从长远来看，我们设想了一系列涉及13C和2H系统给药的临床研究方案，以确定全身葡萄糖产生，肝脂肪酸氧化等的动力学，这对于理解抗胰岛素耐药态生理的基础。同时，可以使用器官特异性的MR成像和光谱法来探测诸如骨骼肌和肝脏等关键器官的代谢。基于我们对代谢的稳定同位素分析的成功，以及我们最近在磁化转移对比剂（最偏见的剂）方面的进展，可以在实验动物中实现此目标，并且将在人类受试者中进行概念验证的发展。 特定目的＃1是在啮齿动物模型中实施和评估新的代谢成像方法。 MRI的葡萄糖成像将在三个大鼠种群中进行研究：对照动物，甲状腺甲状腺大鼠和扎克脂肪大鼠。通过操纵营养状态和胰高血糖素，葡萄糖的浓度和分布将在整个动物中改变。同时测量葡萄糖更新，尿素更新，酮产生，全身脂解和肝13氧化将通过同位素方法确定。 具体目标是继续开发人类受试者中肝13-氧化，全身脂解，糖异生和肝TCA循环通量的方法。临床和科学界希望能够定期测量肝脏中的脂肪酸氧化。在Core 3的这一目标中，Core 1中开发的方法将扩展到患者和志愿者。将在三个人群中测量肝糖异生和13个氧化：禁食，高脂肪饮食和2型糖尿病。我们已经显示出在这些各种代谢状态的葡萄糖生产途径的代谢变化，其中一些是巨大的变化。最后，特定的目标是评估T2糖尿病患者骨骼肌的细胞内脂肪含量和线粒体功能。在T2D患者中，已经假定了细胞内脂肪含量异常，线粒体功能的普遍缺陷。在禁食对照受试者的小腿肌肉和与2型糖尿病的年龄相匹配的患者中，将进行三个测量值：细胞内脂肪含量，ATP合成率（通过31p NMR磁化转移）和柠檬酸周期通量（通过1 h decefecle，1h decoutefecle，13c观察NMR）。