Role of Mitochondrial Dysfunction in Insulin Resistance

线粒体功能障碍在胰岛素抵抗中的作用

• 批准号: 7676040
• 负责人: GERALD I SHULMAN
• 金额: $ 24.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7676040
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP Synthesis Pathway; Acyl Coenzyme A; Address; Age; Arts; Biogenesis; Biopsy Specimen; Brain; Categories; Citric Acid Cycle; Condition; Data; Defect; Development; Diabetes Mellitus; Disease; Dyslipidemias; Energy Metabolism; Event; Fast-Twitch Muscle Fibers; Fatty Acids; Fiber; First Degree Relative; Genes; Goals; Heparin; Hepatic; Hyperlipidemia; Hypertension; Individual; Infusion procedures; Insulin; Insulin Resistance; Isoleucine-Specific tRNA; Lipids; Liver; MAPK8 gene; Magnetic Resonance Spectroscopy; Methods; Mitochondria; Muscle; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Parents; Pathogenesis; Pathologic; Patients; Phosphorylation; Phosphotransferases; Plasma; Play; Principal Investigator; Production; Protein Kinase; Protein Kinase C; Protein-Serine-Threonine Kinases; Rate; Research Personnel; Risk; Rodent; Role; Serine; Skeletal Muscle; Soleus Muscle; Spectrum Analysis; Techniques; Therapeutic Agents; Transfer RNA; Triglycerides; Tyrosine Phosphorylation; Weight; cohort; density; diabetic; falls; fatty acid metabolism; glucose transport; human study; insight; insulin sensitivity; insulin signaling; intrahepatic; microchip; mitochondrial dysfunction; novel; novel therapeutics; patient oriented; prevent; programs

Over ninety percent of diabetics fall into the category of type 2 diabetes and while the primary factors causing this disease are unknown it is clear that insulin resistance plays a major role in its development. Furthermore insulin resistance is the best predictor for the later development of diabetes. Recent preliminary studies by our group have implicated increases in intramyocellular lipid content due to mitochondrial dysfunction as a major factor in causing insulin resistance in skeletal muscle of offspring of parents with type 2 diabetes (IR offspring). The overall goal of this project is to determine the rote of mitochondrial dysfunction in the pathogenesis of insulin resistance in IR offspring. This will be done using state-of-the-art magnetiq resonance spectroscopy in combination with GC-MS and LC/MS/MS techniques. The specific aims that will be addressed in this patient oriented project are to: 1) Assess mitochondrial function by 13C/31P MRS in skeletal muscle of young lean insulin resistant offspring of parents with type 2 diabetic subjects and ageweight-activity-matched control subjects, 2) Assess mitochondrial density, insulin signaling, IRS-1 serine phosphorylation status, protein kinase Cbeta activation, IKKbeta activation, JNK1 activation, fatty acyl CoA concentrations in muscle biopsy samples obtained from young lean insulin resistant offspring of parents with type 2 diabetic subjects and age-weight-activity-matched control subjects, 3) Assess mitochondrial function by 13C/31P MRS in liver of young lean insulin resistant offspring of parents with type 2 diabetic subjects and age-weight-activity-matched control subjects, 4) Assess mitochondrial function by 13C/31P MRS in skeletal muscle of patients with hypertension and hyperlipidemia due to a novel homoplasmic mitochondrial tRNA/ile mutation (identified by R. Lifton) and age-weight-activity matched control subjects. It is anticipated that the results of these studies will yield new and important insights into the role of mitochondrial dysfunction and resultant dysregulation of intramyocellular fatty acid metabolism in the pathogenesis of insulin resistance in offspring of parents with type 2 diabetes. This information will enable the rational development of novel therapeutic agents to prevent or reverse this pathologic condition.

超过90％的糖尿病患者属于2型糖尿病类别，尽管引起该疾病的主要因素尚不清楚，但很明显，胰岛素抵抗在其发育中起主要作用。 此外，胰岛素抵抗是后来糖尿病发展的最佳预测因子。我们小组的最新初步研究暗示，由于线粒体功能障碍，由于线粒体功能障碍而导致2型糖尿病（IR后代）父母后代的骨骼肌的胰岛素抵抗的主要因素增加，这意味着导致胰岛素抵抗的主要因素。该项目的总体目标是确定IR后代胰岛素抵抗发病机理中线粒体功能障碍的死记硬背。这将使用最新的磁磁共振光谱与GC-MS和LC/MS/MS技术结合完成。 The specific aims that will be addressed in this patient oriented project are to: 1) Assess mitochondrial function by 13C/31P MRS in skeletal muscle of young lean insulin resistant offspring of parents with type 2 diabetic subjects and ageweight-activity-matched control subjects, 2) Assess mitochondrial density, insulin signaling, IRS-1 serine phosphorylation status, protein kinase Cbeta activation, IKKbeta activation, JNK1 activation, fatty acyl CoA concentrations in muscle biopsy samples obtained from young lean insulin resistant offspring of parents with type 2 diabetic subjects and age-weight-activity-matched control subjects, 3) Assess mitochondrial function by 13C/31P MRS in liver of young lean insulin resistant offspring of parents with type 2 diabetic subjects and 年龄重量活性匹配的对照受试者，4）由于新型的同质性线粒体tRNA/ILNA突变（由R. LIFTON鉴定）和年龄率效率与对照受试者相匹配，因此在患有高血压和高脂血症患者的骨骼肌中评估了13C/31p MRS的线粒体功能。可以预料，这些研究的结果将对线粒体功能障碍的作用以及对2型2型糖尿病型父母的胰岛素抵抗的发病机理的发病机理产生新的重要见解。这些信息将使新型治疗剂的合理发展能够预防或扭转这种病理状况。