Biomarkers of Dietary Flavonoid Intake, Carbonyl Stress, and Metabolic Risk

摘要/摘要 黄酮类化合物是最常见的多酚类化合物，广泛存在于植物性食品中。这个 估计每天的类黄酮类摄入量可达2克。较高的类黄酮类摄入量与 在一些但不是所有研究中，2型糖尿病(T2D)和心血管疾病(CVD)的风险较低。这 不一致可能是因为营养研究在很大程度上依赖于自我报告的饮食摄入量 往往容易产生测量误差。此外，饮食工具不能解释个体的遗传 和/或微生物组差异和饮食代谢反应的差异。虽然经过验证的生物标记 可能代表了测量饮食的另一种方法，但我们还没有建立起的生物标志物 类黄酮类摄入量。为了更好地了解饮食中的类黄酮对健康和慢性病风险的影响， 需要针对其暴露和影响的生物标记物。最近，我们和其他人已经证明了 类黄酮类化合物清除有毒活性羰基物质可能是一种新的机制 黄酮类化合物预防代谢紊乱的靶点。在我们的研究中，我们已经证明了类黄酮类 可以清除RCS形成相关的RCS共轭，从而防止晚期RCS的形成 小鼠体内的糖基化终末产物(AGEs)。此外，我们还鉴定了几种新的类黄酮代谢物。 与氧化应激有关。然而，目前还不清楚这些发现是否可以外推到人类身上。这 应用目的是检验饮食中的类黄酮及其RCS结合和氧化的假设 代谢物，可以作为类黄酮摄入量的生物标志物，反映个体间的差异，反之亦然 与羰基应激和氧化应激相关的代谢性疾病的风险有关。这一假设 将在三个目标上进行测试。目的1证明RCS偶联物的形成和药代动力学。 人体饮食中主要的类黄酮及其代谢物。为了实现这一目标，我们将进行四项 志愿者喂食四种不同富含类黄酮食物的主要类黄酮药动学研究 (绿茶、豆奶、橙汁和蓝莓)。目标2是确定餐后 类黄酮类摄入对人体羰基应激及相关年龄的影响。目标3的目标是 确定1)已鉴定的类黄酮摄入量生物标志物是否能代表两口井的习惯性摄入量 表型观察性研究--男性生活方式验证研究(MLVS)和女性生活方式研究 验证研究(WLV)，对使用多个7天饮食的饮食进行详细和重复的测量 记录(7DDRs)；以及2)类黄酮类摄入的生物标志物是否与T2D的风险前瞻性相关 在一组女护士中，以及RCS、年龄和氧化应激标志物是否是这一过程的中介因素 协会。在这些研究完成后，我们期望我们将确定目标 反映其摄入量和生物学功能的类黄酮类生物标志物。

SUMMARY/ABSTRACT Flavonoids, the most common group of polyphenolic compounds, widely occur in foods of plant origin. The estimated daily intake of flavonoids can be up to 2 g. Higher flavonoid intake has been associated with a lower risk of type 2 diabetes (T2D) and cardiovascular diseases (CVD) in some but not all studies. This inconsistency may be because nutrition research relies heavily on self-reported measures of dietary intake that are often prone to measurement error. Furthermore, dietary instruments do not account for individual genetic and/or microbiome differences and differences in metabolic response to diet. While validated biological markers may represent an alternative approach for measuring diet, there are no we ll-established biomarkers of flavonoid intake. To better understand the effects of dietary flavonoids on health and risk of chronic diseases, biomarkers for their exposure and effects are needed. Recently, we and others have demonstrated that flavonoids can scavenge toxic reactive carbonyl species (RCS) and carbonyl stress can be a new mechanistic target of flavonoids for prevention of metabolic disorders. In our studies, we have demonstrated that flavonoids can scavenge RCS to form related RCS conjugates, and therefore, prevent the formation of advanced glycation end products (AGEs) in mice. In addition, we also identified several novel flavonoid metabolites related to oxidative stress. However, it is unknown whether these findings can be extrapolated to humans. This application is aimed to test the hypothesis that dietary flavonoids and their RCS conjugates and oxidized metabolites, can serve as biomarkers of flavonoid intake, reflect inter-individual differences, and be inversely associated with the risk of carbonyl stress and oxidative stress associated metabolic diseases. This hypothesis will be tested in three aims. Aim 1 is to demonstrate the formation and pharmacokinetics of RCS conjugates of the major dietary flavonoids and their metabolites in humans. In this aim, we will conduct four acute pharmacokinetic studies of the major dietary flavonoids by giving volunteers four different flavonoid-rich foods (green tea, soy milk, orange juice, and blueberries), respectively. Aim 2 is to determine the post-prandial effects of flavonoid intake on carbonyl stress and related AGEs in humans. The goals of Aim 3 are to determine 1) whether biomarkers of flavonoid intake identified can represent habitual intake from two well phenotyped observational studies – the Men’s Lifestyle Validation Study (MLVS) and the Women’s Lifestyle Validation Study (WLVS), which have detailed and repeated measurements of diet using multiple 7-day diet records (7DDRs); and 2) whether biomarkers of flavonoid intake are prospectively associated with risk of T2D in a cohort of female nurses and whether RCS, AGEs, and oxidative stress markers are mediators of this association. At the completion of these studies, our expectation is that we will have identified objective biomarkers of flavonoids that reflect their intake and biological functions.