Skeletal Mitochondrial Function, Body Weight, and Diabetes, Project 5 of 10

骨骼线粒体功能、体重和糖尿病，项目 5（共 10 个）

• 批准号: 7653675
• 负责人: Craig R Malloy
• 金额: $ 38.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653675
• 关键词: 1,2-diacylglycerol; ATP Synthesis Pathway; Acetates; Acute; Antipsychotic Agents; Body Weight; Body Weight decreased; Ceramides; Characteristics; Chemical Shift Imaging; Chemicals; Citric Acid Cycle; Databases; Diabetes Mellitus; Diet; Diglycerides; Energy Intake; Euglycemic Clamping; Event; Fatty acid glycerol esters; Glucose; Glucose Clamp; Goals; Heart; Human; Infusion procedures; Insulin Resistance; Intracellular Accumulation of Lipids; Link; Lipids; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Monitor; Muscle; Muscle Mitochondria; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Parents; Patients; Play; Research; Resolution; Resources; Rest; Role; Sampling Errors; Signal Transduction; Skeletal Development; Skeletal Muscle; Soleus Muscle; Testing; Triglycerides; Uncertainty; Weight Gain; bariatric surgery; base; carbohydrate metabolism; clinical phenotype; diabetic; fatty acid metabolism; fatty acid oxidation; healthy volunteer; human subject; improved; inorganic phosphate; instrument; insulin sensitivity; insulin signaling; interest; magnetic field; metabolic abnormality assessment; mitochondrial dysfunction; obesity treatment; offspring; olanzapine; oxidation; patient population; research study; skeletal; stable isotope; standard measure; success; therapy development

Skeletal muscle plays a central role in systemic carbohydrate metabolism by oxidizing or storing glucose. The mechanisms of reduced glucose clearance by skeletal muscle, the hallmark of type 2 diabetes, are poorly understood and for this reason a proposed role of mitochondrial dysfunction has attracted considerable interest. According to this picture, reduced fatty acid oxidation by mitochondria leads to buildup of intracellular triglyceride stores, followed by accumulation of byproducts of intracellular fatty acid metabolism that interfere with insulin signaling. However, in spite of intense scientific and public interest in obesity and type 2 diabetes, this hypothesis is difficult to test because of the limitations of standard metabolic studies of muscle. New NMR methods have been developed using instruments operating in the range of 1.5 - 3.0 T to noninvasively probe mitochondrial function and intramyocellular triglycerides, but these methods are difficult to apply because of low signal and relatively poor chemical shift resolution. Our recent observations on healthy volunteers indicate that both limitations will be substantially improved at 7 T. The project will focus on the hypothesis that abnormal function of skeletal muscle mitochondria causes insulin resistance through accumulation of triglycerides. Mitochondrial function will be assessed by two methods, the rate of TCA cycle flux measured by oxidation of [2-13C]acetate and by the rate of ATP synthesis at rest. Intramyocellular lipids will be measured directly by single-voxel 1H NMR spectroscopy. In this project we will examine four populations: patients with type 2 diabetes, lean offspring of patients with type 2 diabetes, patients with type 2 diabetes before and after weight loss, and patients before and after acute weight gain. If the hypothesis is correct, all patients with type 2 diabetes and lean offspring of diabetic parents should have both abnormal mitochondrial function and excess intramyocellular lipids, whereas weight gain should not cause changes in mitochondrial function. This project requires close interaction with Drs. Cohen and Hobbs (Project 7), Drs. Elmquist and Tamminga (Project 2), and Drs. Parks, Browning and Burgess (Project 6).

骨骼肌通过氧化或储存葡萄糖在全身碳水化合物代谢中起核心作用。 2型糖尿病的标志是骨骼肌对葡萄糖的清除减少，其机制如下： 人们对此知之甚少，因此，线粒体功能障碍的作用引起了人们的注意。 相当大的兴趣。根据这张图片，线粒体减少脂肪酸氧化导致 细胞内甘油三酯储存的积累，随后是细胞内脂肪酸副产物的积累 干扰胰岛素信号的代谢。然而，尽管科学界和公众对 肥胖和2型糖尿病，由于标准的局限性，这一假设很难检验。 肌肉代谢研究。新的核磁共振方法已经使用在地球上运行的仪器开发出来 范围为1.5 - 3.0 T，以非侵入性探测线粒体功能和肌细胞内甘油三酯，但 由于低信号和相对差的化学位移分辨率，这些方法难以应用。我们 最近对健康志愿者的观察表明，这两种限制在7 T下将得到实质性改善。 该项目将重点研究骨骼肌线粒体功能异常导致 胰岛素抵抗通过甘油三酯的积累。线粒体功能将通过两个 方法，TCA循环通量的速率通过[2- 13 C]乙酸的氧化和ATP的速率测量 静止合成将通过单体素1H NMR光谱法直接测量肌细胞内脂质。在 在这个项目中，我们将研究四个人群：2型糖尿病患者， 2型糖尿病患者体重减轻前后， 急性体重增加。如果这一假设是正确的，所有2型糖尿病患者和糖尿病患者的瘦后代 父母应该有异常的线粒体功能和过量的肌细胞内脂质，而 体重增加不应引起线粒体功能的变化。该项目需要与 Drs. Cohen和Hobbs（项目7）、Elmquist和Tamminga博士（项目2）以及Parks、布朗宁和 伯吉斯（项目6）。