Role of Mitochondrial Dysfunction in Insulin Resistance

超过90%的糖尿病患者属于2型糖尿病的范畴，虽然导致这种疾病的主要因素尚不清楚，但很明显胰岛素抵抗在其发展中起着重要作用。 此外，胰岛素抵抗是糖尿病后期发展的最佳预测因素。我们小组最近的初步研究表明，由于线粒体功能障碍导致的肌细胞内脂质含量增加是导致2型糖尿病父母后代（IR后代）骨骼肌胰岛素抵抗的主要因素。本项目的总体目标是确定线粒体功能障碍在IR后代胰岛素抵抗发病机制中的作用。这将使用最先进的磁共振光谱结合GC-MS和LC/MS/MS技术进行。在这个以病人为导向的项目中，将解决的具体目标是：1）通过13 C/31 P MRS评估2型糖尿病受试者和年龄-体重-活动匹配的对照受试者的父母的年轻瘦胰岛素抵抗后代的骨骼肌中的线粒体功能，2）评估线粒体密度、胰岛素信号传导、IRS-1丝氨酸磷酸化状态、蛋白激酶C β活化、IKK β活化，JNK 1活化，从患有2型糖尿病受试者的父母的年轻瘦型胰岛素抵抗后代和年龄-体重-活性匹配的对照受试者获得的肌肉活检样品中的脂肪酰CoA浓度，3）通过患有2型糖尿病受试者的父母的年轻瘦型胰岛素抵抗后代的肝脏中的13 C/31 P MRS评估线粒体功能， 4）通过13 C/31 P MRS评估高血压和高脂血症患者骨骼肌中线粒体功能，所述高血压和高脂血症是由于一种新的同质线粒体tRNA/ile突变（由R.利夫顿）和年龄-体重-活动匹配的对照组。预计这些研究的结果将产生新的和重要的见解线粒体功能障碍的作用和由此产生的肌细胞内脂肪酸代谢失调的发病机制中的胰岛素抵抗的父母与2型糖尿病的后代。这些信息将使合理开发新的治疗药物，以防止或扭转这种病理条件。

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.