Mechanism of Insulin Resistance in the Aged.

描述（由申请人提供）：2型糖尿病（T2DM）是老年人中最常见的慢性疾病之一，影响约23%的60岁及以上的美国人。据估计，2型糖尿病的总经济负担每年超过1000亿美元，其中很大一部分可归因于该年龄组的人。胰岛素抵抗在与衰老相关的T2DM发病机制中起着重要作用，但其发病机制尚不清楚。在这方面，我们小组最近的多核（1H/13C）磁共振波谱（MRS）研究表明，在健康、瘦弱的老年人中，骨骼肌中基础线粒体功能的降低与细胞内和肝脏甘油三酯含量的增加以及胰岛素抵抗有关。这使我们假设，与衰老相关的线粒体功能降低导致脂肪氧化减少，使这些个体容易增加细胞内和肝内脂质含量，从而导致胰岛素信号缺陷和胰岛素抵抗。本基金提出的研究将建立在这些新发现的基础上，进一步探索肌肉线粒体功能改变在老年人胰岛素抵抗和2型糖尿病发病机制中的潜在作用，以及骨骼肌胰岛素抵抗在使这些个体增加肝脏新生脂肪生成导致动脉粥样硬化性血脂异常、非酒精性脂肪性肝病（NAFLD）和代谢综合征中的潜在作用。具体而言，我们将应用最先进的1H/13C MRS技术结合新开发的液相色谱串联质谱法来检测：1)衰老对胰岛素刺激的线粒体功能的影响，2)老年人骨骼肌胰岛素抵抗在促进肝脏新生脂肪生成中的作用，3)衰老对肌肉活检中基础和胰岛素刺激的肌肉线粒体葡萄糖和脂肪氧化的相对贡献的影响，4)开发和测试新的13C MRS技术，以无创地确定衰老对基础和胰岛素刺激的肌肉线粒体葡萄糖和脂肪氧化的相对贡献的影响。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in the elderly affecting approximately 23% of Americans 60 years of age and older. Estimates of the total economic burden of T2DM exceed $100 billion/year, of which a major proportion can be attributed to persons in this age group. It is well established that insulin resistance plays a major role in the pathogenesis of T2DM associated with aging but the mechanisms responsible for its development remain poorly understood. In this regard recent multinuclear (1H/13C) magnetic resonance spectroscopy (MRS) studies by our group have demonstrated reduced basal mitochondrial function in skeletal muscle associated with increased intramyocellular and hepatic triglyceride content and insulin resistance in healthy, lean, elderly individuals. This led us to hypothesize that reduced mitochondrial function associated with aging leads to reduced fat oxidation predisposing these individuals to increases in intramyocellular and intrahepatic lipid content leading to defects in insulin signaling and insulin resistance. The studies proposed in this grant will build on these novel findings to further explore the potential role of altered muscle mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance in predisposing these individuals to increased hepatic de novo lipogenesis resulting in atherogenic dyslipidemia, non alcoholic fatty liver disease (NAFLD), and the metabolic syndrome. Specifically, we will apply state-of-the-art 1H/13C MRS techniques in combination with newly developed liquid chromatography tandem mass spectrometry methods to examine: 1) the impact of aging on insulin-stimulated mitochondrial function, 2) the role of skeletal muscle insulin resistance in the elderly in promoting increased hepatic de novo lipogenesis, 3) the impact of aging on the relative contributions of basal and insulin stimulated muscle mitochondrial glucose and fat oxidation in muscle biopsies, and 4) development and test of novel 13C MRS techniques to non-invasively determine the effects of aging on basal and insulin stimulated relative contributions of muscle mitochondrial glucose and fat oxidation in muscle.