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

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着核心作用。 2型糖尿病的标志--骨骼肌减少葡萄糖清除的机制是 人们对线粒体功能障碍知之甚少，因此，提出的线粒体功能障碍的作用吸引了 相当感兴趣。根据这张图，线粒体减少的脂肪酸氧化导致 细胞内甘油三酯储存的积累，随后细胞内脂肪酸副产物的积累 干扰胰岛素信号的新陈代谢。然而，尽管科学和公众对此产生了强烈的兴趣 肥胖和2型糖尿病，这一假设很难检验，因为标准的限制 肌肉代谢研究。新的核磁共振方法已经开发出来，使用的仪器运行在 1.5-3.0T范围内无创探测线粒体功能和心肌细胞内甘油三酯，但 由于信号低，化学位移分辨率相对较差，这些方法很难应用。我们的 最近对健康志愿者的观察表明，在7T时，这两个限制都将得到显著改善。 该项目将专注于这样一个假设，即骨骼肌线粒体功能异常导致 通过积累甘油三酯而产生的胰岛素抵抗。线粒体功能将通过两种方法进行评估 方法：用[2-13C]乙酸酯氧化法和三磷酸腺苷速率法测定TCA循环通量 静止的合成。心肌细胞内的脂质将通过单体素1H核磁共振波谱直接测量。在……里面 在这个项目中，我们将检查四个人群：2型糖尿病患者，患有糖尿病的患者的瘦子 2型糖尿病、2型糖尿病患者减肥前后、减肥前后患者 体重急剧增加。如果假设是正确的，所有患有2型糖尿病和糖尿病精瘦后代的患者 父母应该既有线粒体功能异常，又有过多的心肌细胞内脂质，而 体重增加不应导致线粒体功能的改变。该项目需要与 Cohen和Hobbs博士(项目7)，Elmquist和Tamminga博士(项目2)，Parks博士，Browning和 伯吉斯(项目6)。

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).