Metformin Effect on Brain Function in Insulin Resistant Elderly People

项目摘要/摘要 随着人口老龄化，阿尔茨海默病(AD)和其他形式的痴呆症迅速增加， 并且在胰岛素抵抗人群中显示出明显的优势。二甲双胍是一种胰岛素增敏剂， 作为一种抗衰老药物正在进行临床试验。然而，关于这方面的客观数据很少。 二甲双胍对大脑的作用，大脑是受衰老影响的主要器官。胰岛素受体广泛分布于 大脑和它们的破坏会导致神经元功能障碍和类似AD的变化。临床前研究表明 二甲双胍可改善许多AD相关的改变，并刺激线粒体的生物发生。然而， 对2型糖尿病患者(T2D)的观察性人体研究显示，相互矛盾或模棱两可的结果 可能与其他并存疾病有关。二甲双胍是一种有很长记录的药物，显示出良好的 老年胰岛素抵抗患者的安全性评价。因此，我们提交当前的 探索性/发展性研究建议，以研究二甲双胍是否增强脑线粒体 核磁共振(NMRS)的功能(ATP产生)与血流和功能 功能磁共振成像(FMRI)通过大脑不同区域，特别是那些富含胰岛素受体的区域建立网络。作为一名 二次测量，我们将测量大脑白质和灰质区域的结构变化 通过核磁共振检查。认知功能将通过使用计算机化的NIH工具箱进行评估。这40周的安慰剂 受控双盲人体研究将随机选择40名患有腹部肥胖症的65岁老年人和 二甲双胍或安慰剂干预导致空腹血糖受损。 这个项目代表了PI的一个新方向，是与Mayo诊所的同事共同努力的结果 具有MRI、NMRS和AD方面的专业知识。研究结果可能导致在提供以下两种情况之一方面的突破 有关二甲双胍对老年高血压患者疗效的明确数据或足够有力的初步数据 胰岛素抵抗，取决于药物是否联合增强了他们的大脑线粒体功能 随着大脑功能网络和认知功能的改善。建议的研究是 寻求更大规模的赠款申请所需的必要步骤，涉及使用二甲双胍作为佐剂 其他既定生活方式的改变会对大脑产生有益影响。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging. Insulin receptors are widely distributed in the brain and their disruption causes neuronal dysfunction and AD like changes. Pre-clinical studies suggest that metformin ameliorates many AD-related changes and stimulate mitochondrial biogenesis. However, observational human studies among type 2 diabetics (T2D) show either conflicting or equivocal results which could be related to other co-morbidities. Metformin is a drug with a long track-record showing an excellent safety profile among elderly people with insulin resistance. We therefore submit the current exploratory/developmental research proposal to investigate whether metformin enhances brain mitochondrial function (ATP production) by nuclear Magnetic Spectroscopy (NMRS) and blood flow and the functional network by functional MRI (fMRI) of different regions of brain, especially those rich in insulin receptors. As a secondary measurement, we will measure structural changes in the white and grey matter areas of the brain by MRI. Cognitive function will be assessed by utilizing the computerized NIH Toolbox. This 40 week placebo controlled double-blind human study will randomize 40 elderly people >65 years with abdominal adiposity and impaired fasting glucose to either metformin or placebo intervention. This project represents a new direction for the PI and is a collaborative effort with colleagues at the Mayo Clinic with expertise in MRI, NMRS, and AD. The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances their brain mitochondrial function in conjunction with improvement of brain functional network and cognitive functions. The proposed research is the essential step needed to pursue a larger grant application involving the use of metformin as an adjutant to other established life style changes with beneficial effects on the brain.