Metformin Effect on Brain Function in Insulin Resistant Elderly People

项目总结/摘要 阿尔茨海默病（AD）和其他形式的痴呆随着人口老龄化而迅速增加， 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临床试验中接受检查。然而，关于以下方面的客观数据很少 二甲双胍对大脑的影响，大脑是受衰老影响的主要器官。胰岛素受体广泛分布于 脑及其破坏引起神经元功能障碍和AD样变化。临床前研究表明， 二甲双胍可改善许多AD相关变化并刺激线粒体生物合成。然而，在这方面， 2型糖尿病（T2 D）的观察性人类研究显示了相互矛盾或模棱两可的结果， 可能与其他合并症有关二甲双胍是一种具有长期记录的药物， 在胰岛素抵抗的老年人中的安全性。因此，我们提出目前的 探索性/开发性研究提案，以研究二甲双胍是否能增强脑线粒体 功能（ATP生产）通过核磁共振波谱（NMRS）和血流和功能 通过功能性磁共振成像（fMRI）对大脑不同区域的网络进行了研究，特别是那些富含胰岛素受体的区域。作为 第二次测量，我们将测量大脑白色和灰质区域的结构变化 通过MRI。认知功能将通过使用计算机化的NIH量表进行评估。40周安慰剂 一项对照双盲人体研究将随机选择40名年龄>65岁的腹部肥胖老年人， 二甲双胍或安慰剂干预的空腹血糖受损。 该项目代表了PI的新方向，是与马约诊所同事的合作成果 在核磁共振核磁共振波谱和阿尔茨海默病方面有专长研究结果可能会导致突破， 关于二甲双胍对老年人影响的确切数据或足够强的初步数据， 胰岛素抵抗，药物是否增强他们的大脑线粒体功能， 改善脑功能网络和认知功能。拟议的研究是 需要采取必要的步骤，以寻求更大的赠款申请，涉及使用二甲双胍作为一个辅助， 其他既定的生活方式的变化，对大脑有益的影响。

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.