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

总结/摘要 黄酮类化合物是多酚类化合物中最常见的一类，广泛存在于植物源性食品中。的 估计每天摄入的类黄酮可达2克。较高的类黄酮摄入量与 2型糖尿病（T2 D）和心血管疾病（CVD）的风险较低，在一些但不是所有的研究中。这 不一致可能是因为营养研究严重依赖于自我报告的饮食摄入量， 往往容易出现测量误差。此外，饮食工具没有考虑到个体遗传因素， 和/或微生物组差异和对饮食的代谢反应的差异。虽然经过验证的生物标志物 可能代表了一种测量饮食的替代方法，但目前还没有确定的生物标志物， 类黄酮摄入量为了更好地了解膳食黄酮对健康和慢性疾病风险的影响， 需要其暴露和影响的生物标志物。最近，我们和其他人已经证明， 黄酮类化合物能抑制毒性反应性羰基自由基（RCS），羰基应激可能是其抑制RCS的新机制 黄酮类化合物用于预防代谢紊乱靶点。在我们的研究中，我们已经证明类黄酮 可以使RCS形成相关的RCS共轭，因此，可以防止高级RCS的形成。 糖基化终产物（AGEs）。此外，我们还鉴定了几种新的黄酮类代谢产物 与氧化应激有关。然而，目前尚不清楚这些发现是否可以外推到人类身上。这 本申请旨在检验膳食类黄酮及其RCS缀合物和氧化 代谢产物，可以作为生物标志物的黄酮类化合物摄入量，反映个体间的差异，并与 与羰基应激和氧化应激相关的代谢疾病的风险相关。这一假设 将在三个目标中进行测试。目的1是证明化合物1的RCS缀合物的形成和药代动力学。 人类主要的膳食类黄酮及其代谢物。为此，我们将进行四次急性 通过给予志愿者四种不同的富含类黄酮的食物对主要膳食类黄酮的药代动力学研究 （绿色茶、豆奶、橙子汁和蓝莓）。目的2是确定餐后 类黄酮摄入对人体羰基应激和相关AGEs的影响。目标3的目标是 确定1）所鉴定的类黄酮摄入的生物标志物是否可以代表来自两个井的习惯性摄入 表型观察性研究-男性生活方式验证研究（MLVS）和女性生活方式验证研究 验证研究（WLVS），使用多个7天饮食对饮食进行详细和重复测量 记录（7 DDRs）; 2）类黄酮摄入的生物标志物是否与T2 D风险前瞻性相关 在一组女护士中，RCS、AGEs和氧化应激标志物是否是这一过程的介质， 协会在完成这些研究后，我们预期会确定目标， 类黄酮的生物标志物，反映其摄入量和生物功能。

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.