Molecular Regulation of Muscle Glucose Metabolism in Man

人体肌肉葡萄糖代谢的分子调节

基本信息

批准号：
10394224
负责人：
LAWRENCE J MANDARINO
金额：
$ 69.06万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394224
关键词：
ATP Synthesis Pathway Acetylation Adenine Nucleotide Translocase Affinity Binding Proteins Biochemical Bioenergetics Biological Assay Biopsy Carbohydrates Cardiovascular Diseases Cell Line Cells Clostridium perfringens theta-toxin Closure by clamp Consumption Creatine Kinase Diabetes Mellitus Disease Exercise Exhibits Fatty acid glycerol esters Genetic Genus Hippocampus Glucose Glucose Clamp Goals Human Hyperinsulinism Impairment In Vitro Indirect Calorimetry Insulin Insulin Resistance Lead Lipids Liver Lysine Mass Spectrum Analysis Measurement Metabolic Methods Mitochondria Mitochondrial Proteins Molecular Morbid Obesity Mus Muscle Muscle Cells Muscle Fibers Nature Non-Insulin-Dependent Diabetes Mellitus Null Lymphocytes Obesity Oxides PDH kinase Palmitoylcarnitine Pathway interactions Patients Phosphorylation Plasma Proteins Proteome Proteomics Public Health Pyruvate Regulation Respiration Rest Skeletal Muscle Techniques Testing Time Tissues Type 2 diabetic bariatric surgery base diabetic patient effectiveness evaluation experimental study genetic variant glucose metabolism in vivo mRNA Expression man metabolic phenotype non-diabetic novel obese patients oxidation predictive modeling preference pyruvate dehydrogenase resistance mechanism respiratory solute transcriptome transcriptomics

项目摘要

Twenty-five years ago we showed that skeletal muscle in type 2 diabetes preferentially oxidizes carbohydrate over fat and exhibits what we termed “metabolic inflexibility”. This results in accumulation of fat in insulin sensitive tissues and leads to insulin resistance. Genetic activation of the pyruvate oxidation pathway through deletion of pyruvate dehydrogenase (PDH) kinase showed that an increase in glucose oxidation is sufficient to induce insulin resistance by this mechanism. Although many studies have described how the consequences of lipid accumulation lead to insulin resistance, little is known of the mechanisms causing metabolic inflexibility to begin with. In the past project period, we developed evidence for two potential mechanisms. The first of these derives from our findings that acetylation on lysine 23 of the mitochondrial solute carrier adenine nucleotide translocase 1 (ANT1) lowers the affinity of the protein for ADP. This is associated with a higher KmADP for respiration and ATP synthesis. Modeling predicts this leads to higher free ADP and AMP concentrations. Higher [ADP]f would enhance glycolytic rates, raise [pyruvate], and activate PDH via inactivation of PDH kinase, leading to higher rates of glucose oxidation. Second, we used a proteomics screen of livers of high fat fed mice and discovered an uncharacterized mitochondrial protein, KIAA0564 (VWA8), that dampens fat oxidation, is elevated in skeletal muscle of type 2 diabetic or morbidly obese patients undergoing bariatric surgery, and has genetic variants that are associated with obesity, diabetes, and abnormal plasma lipid levels. Given this, we believe it is timely to return to the question of what mechanisms drive elevated carbohydrate oxidation and metabolic inflexibility in muscle of patients with type 2 diabetes and morbid obesity. The overall goal of this proposal is to determine how acetylation of ANT1 at lysine 23 and expression of the novel mitochondrial protein VWA8 influence fuel selection in patients with Type 2 diabetes mellitus. We propose 1. To determine the mechanisms responsible for metabolic inflexibility in skeletal muscle of patients with type 2 diabetes mellitus, 2. To determine the mechanisms responsible for impaired control of respiration and higher resting carbohydrate oxidation in skeletal muscle of patients with type 2 diabetes mellitus, and 3. To further characterize the mechanisms by which VWA8 regulates fuel selection. !

25年前，我们表明2型糖尿病中的骨骼肌优先氧化在脂肪上表现出我们所谓的“代谢僵化性”。这导致胰岛素中脂肪的积累敏感的组织并导致胰岛素抵抗。丙酮酸氧化途径的遗传激活丙酮酸脱氢酶（PDH）激酶的缺失表明，葡萄糖氧化的增加足以使通过这种机制诱导胰岛素抵抗。尽管许多研究都描述了如何的后果脂质积累会导致胰岛素抵抗，几乎不知道导致代谢僵化的机制从。在过去的项目时期，我们为两种潜在机制开发了证据。其中的第一个来自我们的发现，即线粒体固体载体腺嘌呤核苷酸上赖氨酸的乙酰化23 易位酶1（ANT1）降低了蛋白质对ADP的亲和力。这与较高的kmadp有关呼吸和ATP合成。建模预测这会导致更高的自由ADP和AMP浓度。较高的[ADP] F会提高糖酵解速率，提高[丙酮酸]并通过PDH失活而激活PDH 激酶，导致更高的葡萄糖氧化速率。其次，我们使用了高脂生活的蛋白质组学屏幕喂小鼠并发现了一种未表征的线粒体蛋白Kiaa0564（vwa8），该死的脂肪氧化在2型糖尿病或病态肥胖患者的骨骼肌中升高手术，具有与肥胖，糖尿病和异常血浆脂质水平相关的遗传变异。鉴于此，我们认为及时回到哪种机制驱动碳水化合物的问题 2型糖尿病和病态肥胖症患者肌肉的氧化和代谢僵化。总体该提议的目标是确定赖氨酸23的ANT1的乙酰化和小说的表达线粒体蛋白VWA8影响2型糖尿病患者的燃料选择。我们提案1。确定负责骨骼肌代谢不灵活的机制 2型糖尿病患者，2。确定负责控制受损的机制 2型患者骨骼肌的呼吸和更高的静息碳氧化糖尿病和3。进一步表征VWA8调节燃料选择的机制。呢