Mechanism of Insulin Resistance in the Aged.

描述（由申请人提供）：2型糖尿病（T2 DM）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。T2 DM的总经济负担估计超过1000亿美元/年，其中大部分可归因于该年龄组的患者。众所周知，胰岛素抵抗在与衰老相关的2型糖尿病发病机制中起着重要作用，但对其发展机制仍知之甚少。在这方面，我们小组最近的多核（1H/13 C）磁共振光谱（MRS）研究表明，健康、瘦肉型老年人骨骼肌中基础线粒体功能下降与肌内和肝脏甘油三酯含量增加以及胰岛素抵抗相关。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，使这些个体易于增加肌细胞内和肝内脂质含量，导致胰岛素信号传导和胰岛素抵抗缺陷。本基金中提出的研究将以这些新发现为基础，进一步探索肌肉线粒体功能改变在老年人胰岛素抵抗和T2 DM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易于增加肝脏新生脂肪生成中的潜在作用，从而导致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。具体而言，我们将应用最先进的1H/13 C MRS技术与新开发的液相色谱串联质谱法相结合，以检查：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增加中的作用，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，以及4）新型13 C MRS技术的开发和测试侵入性地确定衰老对肌肉线粒体葡萄糖和肌肉中脂肪氧化的基础和胰岛素刺激的相对贡献的影响。 公共卫生相关性：2型糖尿病（T2 DM）是老年人最常见的慢性疾病之一，T2 DM的总经济负担估计超过1300亿美元/年。本研究将建立在我们最近的观察基础上，这些观察表明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使这些个体易患致动脉粥样硬化性血脂异常的潜在作用。预计这些以患者为导向的假设驱动研究的结果将为与衰老相关的胰岛素抵抗和致动脉粥样硬化性血脂异常的发病机制提供重要的新见解，并为预防T2 DM和促进健康衰老提供新的靶点。

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. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in older adulthood and estimates of the total economic burden of T2DM exceed $130 billion/year. The studies proposed in this grant will build on our recent observations demonstrating a potential role of altered mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance predisposing these individuals to atherogenic dyslipidemia. It is anticipated that the results from these patient-oriented hypothesis-driven studies will provide important new insights into the pathogenesis of insulin resistance and atherogenic dyslipidemia associated with aging and provide new targets to prevent T2DM and promote healthy aging.