Diet and Exercise Trial to Improve Insulin Resistance, Increase Cerebral Blood Flow, Alter Metabolomic Biomarkers, and Decrease Alzheimer's Disease Risk

项目摘要 代谢综合征（MetS）与糖尿病和心血管疾病的发生有关， 疾病;然而，它也与认知能力下降和痴呆症有关。我们已经证明，MetS是 与中年晚期成人脑血流量（CBF）和记忆功能降低相关， 患阿尔茨海默病（AD）的风险。胰岛素抵抗（IR）是代谢综合征的核心， IR的特征是空腹血糖（FBG）和餐后高血糖。 虽然我们和其他人已经证明了IR和CBF之间的联系，以及来自一个人的认知， 从观察的角度来看，没有研究调查CBF和认知干预后， 运动和碳水化合物限制饮食（CRD），旨在改善或正常化IR和葡萄糖 体内平衡我们建议确定改善或正常化葡萄糖稳态对CBF的影响 和认知，通过饮食和运动，在个人与IR和风险的发展为AD。 虽然运动和CRD已被证明可以改善IR和血糖控制，但我们只能有限地 了解这些改进背后的机制。营养代谢组学，全球测量 和代谢谱的解释，评估饮食与内源性基因-蛋白质的相互作用， 级联和肠道微生物组。此外，运动已被证明对人体有影响， 代谢组最后，许多代谢产物与IR和空腹血糖受损有特异性联系 （IFG）。我们建议使用代谢组学来测量代谢物的变化， 改善IR和葡萄糖稳态。 这项探索性研究是否应该揭示， 饮食和锻炼，那么对这些高危个体的早期治疗可能会为疾病进程提供新的途径。 改性早期和有效的风险因素管理战略可能有助于减少 代谢和认知能力下降的风险。此外，如果这项研究揭示了代谢的变化， 与糖尿病的早期迹象一致的异常，代谢组学可能是一种有效的方法， 补充疾病风险分析，以实现我们的精准护理目标。

Project Summary Metabolic syndrome (MetS) is associated with the development of diabetes and cardiovascular disease; however it is also linked with cognitive decline and dementia. We have shown that MetS is associated with lower cerebral blood flow (CBF) and memory function in late middle-aged adults at increased risk for developing Alzheimer’s disease (AD). Insulin resistance (IR) is at the core of MetS, and a hallmark feature of IR is higher fasting blood glucose (FBG) as well as post prandial hyperglycemia. While we and others have demonstrated links between IR and CBF as well as cognition from an observational perspective, no studies have investigated CBF and cognition after an intervention involving exercise and a carbohydrate restricted diet (CRD) designed to improve or normalize IR and glucose homeostasis. We propose to determine the effect of improving or normalizing glucose homeostasis on CBF and cognition, through diet and exercise, in individuals with IR and at risk for the development of AD. While exercise and a CRD have been shown to improve IR and glycemic control, we have only limited knowledge of the mechanisms behind these improvements. Nutritional metabolomics, the global measurement and interpretation of metabolic profiles, assesses the interaction of diet with the endogenous gene-protein cascade and the gut microbiome. Additionally, exercise has been shown to have an impact on the human metabolome. Finally, numerous metabolites have been specifically linked to IR and impaired fasting glucose (IFG). We propose to use metabolomics to measure changes in metabolites as individuals normalize or improve IR and glucose homeostasis. Should this exploratory study reveal increased brain blood flow and improved memory in response to diet and exercise, then early treatment of these individuals at risk might offer new avenues for disease-course modification. Strategies towards early and effective risk factor management could be of value in reducing the risk of metabolic as well as cognitive decline. In addition, should this study reveal changes in metabolic abnormalities consistent with early indications of diabetes, metabolomics could be an effective approach to complement disease risk analysis in our goal toward precision care.