Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

项目摘要 已经确定阿尔茨海默病和其他痴呆症在人类中的发病率 胰岛素抵抗胰岛素抵抗发生在几乎80%的阿尔茨海默病患者中。两 有氧运动和抗阻运动训练可改善外周胰岛素敏感性， 对认知的影响尽管一些研究表明，动物和人类的有氧运动 改善脑葡萄糖摄取和线粒体功能，目前尚不清楚抗阻运动是否 对大脑生物学有任何直接影响，可以有助于改善认知功能。在当前 应用程序，我们建议收集初步数据，以计划未来更大的研究，以检验假设， 提高外周胰岛素敏感性的抗阻运动也增加了大脑中的胰岛素敏感性 通过18-FDG PET扫描测量。此外，我们还将确定大脑中的相同区域是否 显示改善的葡萄糖摄取也有增强的线粒体能量代谢物的证据， 其他神经元健康的生物标志物。我们将使用结构磁共振以及磷和质子磁共振 光谱学来测量大脑微观结构和富含胰岛素受体的大脑区域中的代谢物， 皮质和海马体。此外，我们还将测量不同区域之间的功能连接， 大脑通过功能性MRI来验证一个假设，即改善胰岛素敏感性和增强能量 大脑中的新陈代谢将改善大脑不同区域之间的连通性， 连通性与认知能力的提高有关。本研究中提出的所有技术都很好 在我们的机构建立，PI与神经放射科医生和核医学专家合作， 在1型糖尿病中进行研究，显示胰岛素缺乏相关的大脑能量学变化， 与认知变化同时发生的功能连接。在目前的研究中，我们建议测量MRI （结构和功能），MR光谱和18-FDG PET扫描以及使用 24名胰岛素抵抗参与者的NIH工具箱，他们是NIH RO 1资助的一部分，用于研究 抗阻运动训练对外周血胰岛素敏感性的影响我们认为，这是一个非常具有成本效益的 获得目前尚不存在的初步数据的方法，以进一步开展更大规模的研究， 了解阻力训练如何通过测量大脑连接，能量学和 微观结构本研究的唯一额外费用与涉及MR的神经放射学相关 测量和基于PET扫描的基于放射性同位素的葡萄糖摄取研究。本研究的结果 将使我们能够确定是否有足够的初步数据来支持我们的假设， 运动训练改善胰岛素抵抗者的大脑功能和认知功能。

PROJECT SUMMARY It has been well established that Alzheimer’s disease and other dementias are substantially higher in people with insulin resistance. Insulin resistance occurs in almost 80% of people with Alzheimer’s disease. Both aerobic exercise and resistance exercise training improve peripheral insulin sensitivity and have a beneficial effect on cognition. Although several studies have shown that aerobic exercise in both animals and humans improves brain glucose uptake and mitochondrial function, it is currently unknown whether resistance exercise has any direct effect on brain biology that can contribute to improved cognitive functions. In the current application, we propose to collect preliminary data to plan future larger studies to test the hypothesis that resistance exercise which improves peripheral insulin sensitivity also increases insulin sensitivity in the brain as measured by 18-FDG PET scanning. In addition, we will determine whether the same areas in the brain showing improved glucose uptake also have evidence of enhanced mitochondrial energy metabolites and other biomarkers of neuronal health. We will use structural MRI as well as phosphorus and proton MR spectroscopy to measure brain microstructure and metabolites in brain regions rich in insulin receptors such as cortex and hippocampus. In addition, we also will measure functional connectivity between different regions of the brain by functional MRI to test a hypothesis that improving insulin sensitivity and enhanced energy metabolism in the brain will improve connectivity between different regions of the brain and that this improved connectivity is related to improvements in cognition. All the techniques proposed in the current study are well established at our institution where the PI collaborated with neuro-radiologists and nuclear medicine experts to perform studies in type 1 diabetes showing that insulin deficiency-related changes on brain energetics and functional connectivity concurrent to cognitive changes. In the current study we propose to measure MRI (structural and functional), MR spectroscopy and 18-FDG PET scans as well as neuropsychological tests using NIH Tool box in 24 insulin resistant participants who are part of an NIH RO1 grant to study the mechanism of resistance exercise training effects on peripheral insulin sensitivity. We propose that this is a very cost-effective approach to obtain currently non-existent preliminary data to move forward with further larger studies to understand how resistance training improves cognition by measuring brain connectivity, energetics, and microstructure. The only additional expenses for this study are related to the neuroradiology involving MR measurements and radioisotope-based glucose uptake studies based on PET scan. The results from this study will allow us to determine whether there is sufficient preliminary data to support our hypothesis that resistance exercise training improves brain functions and cognitive functions in insulin resistant people.