Vitamin E Requirements in Women,Obese Women and Diabetic Obese Women

描述(由申请人提供)：流行病学研究表明，通过终生摄入更高的膳食维生素E可以降低慢性病风险。然而，超过90%的美国人每天摄入的1-生育酚不到食品和营养委员会推荐的15毫克(22IU)的40%。通常6毫克的摄入量足够吗？目前没有必要的循证数据来回答这一问题；拟议的研究试图填补这一空白。我们之前的研究表明，人类的氧化应激会更快地耗尽血浆中的维生素E，而充足的维生素C摄入量可以抵消维生素E加速消耗的影响。拟议的研究将使用优化的药代动力学测量方法来解决身体需要多少维生素E来应对氧化应激或维生素C耗尽状态。这项研究的独特之处在于它是NIH内部和外部研究人员之间的合作。拟议的研究将在NIH的临床研究中心与Mark Levine博士和他的团队一起进行，他们在测量维生素C的药代动力学和生物利用度方面拥有丰富的经验。我们的实验室拥有必要的专业知识、经验和设备来测量低浓度的稳定同位素标记的维生素E、其代谢物和过氧化生物标志物。这项提案寻求为Traber小组提供资金，用于分析氚标记的α-生育酚样品和脂质过氧化生物标记物。具体目的1.测定正常体重女性的α-生育酚药代动力学。维生素E动力学研究将可以确定维生素E状况的关键指标，包括吸收分数、向组织的释放速率和全身流出。试点研究1：确定伴餐中的最佳脂肪含量，以优化α-生育酚的吸收。初步研究2：确定周转动力学的最佳α-生育酚剂量。具体目标2和3。测定正常体重妇女、肥胖妇女和肥胖糖尿病妇女维生素C耗竭前后的α-生育酚药代动力学。我们的工作假设是，α-生育酚的浓度是由足够的维生素C(抗坏血酸)浓度维持的。因此，如果抗坏血酸受到限制，α-生育酚向靶组织的输送将会增加。此外，为了保持组织中α-生育酚的浓度，由于肥胖和肥胖伴糖尿病引起的氧化应激导致的周转增加，α-生育酚的释放速率增加。这些研究的成功完成将为健康妇女以及患有氧化应激增加的妇女的每日推荐摄入量的制定提供必要的关键指标，包括对α-生育酚状态的吸收分数、向组织的释放速率和全身排泄。 与公共健康相关：我们已经证明，α-生育酚是最有效的维生素E形式，因为人体主动调节其血浆浓度和向组织的输送，而其他形式的维生素E则活跃地代谢和排泄。拟议的研究将使用优化的药代动力学测量方法，并将这些方法应用于评估“身体需要多少维生素E？”的问题，以及这些需求是否会随着氧化压力的增加或维生素C状态的降低而改变。

DESCRIPTION (provided by applicant): Epidemiologic studies suggest that chronic disease risk can be reduced by a lifetime of consuming higher dietary vitamin E intakes. However, more than 90% of Americans consume less than 40% of the 15 mg (22 IU) 1-tocopherol recommended daily by the Food and Nutrition Board. Is the usual 6 mg consumed sufficient? The necessary evidence-based data are currently unavailable to answer this question; the proposed study seeks to fill this gap. Our previous studies show that oxidative stress in humans more rapidly depletes plasma vitamin E and sufficient vitamin C intake counters the accelerated vitamin E depletion. The proposed studies will use optimized methods for pharmacokinetic measurements to address how much vitamin E is needed by the body in response to either or both oxidative stress or depleted vitamin C status. This study is unique in that it is a collaboration between NIH intra- and extramural investigators. The proposed studies will be carried out with Dr. Mark Levine and his group at the NIH in the Clinical Research Center, who have extensive experience in measuring vitamin C pharmacokinetics and bioavailability. Our laboratory has the necessary expertise, experience and equipment to measure the low concentrations of stable isotope labeled vitamin E, its metabolites, and peroxidation biomarkers. This proposal seeks funding for the Traber group for the analysis of deuterium-labeled alpha-tocopherol samples and lipid peroxidation biomarkers. Specific Aim 1. Determine alpha-tocopherol pharmacokinetics in normal weight women. Vitamin E kinetic studies will allow determination of key measures of vitamin E status including fractional absorption, rates of delivery to tissues, and whole body efflux. Pilot Study 1: Determine the optimal fat content in the accompanying meal necessary to optimize alpha-tocopherol absorption. Pilot Study 2: Determine the optimal alpha-tocopherol dose for turnover kinetics. Specific Aims 2 & 3. Determine alpha-tocopherol pharmacokinetics before and after vitamin C depletion in normal-weight women, obese women and obese women with diabetes. Our working hypothesis is that alpha-tocopherol concentrations are maintained by adequate vitamin C (ascorbic acid) concentrations. Thus, the delivery of alpha-tocopherol to the target tissues will be increased if ascorbic acid is limiting. Furthermore to maintain tissue alpha-tocopherol concentrations, rates of delivery of alpha-tocopherol increase due to increased turnover resulting from oxidative stress caused by obesity and from obesity with diabetes. The successful completion of these studies will provide essential key measures of alpha-tocopherol status, including fractional absorption, rates of delivery to tissues, and whole body efflux, for formulation of recommended daily intakes in healthy women, as well as women with conditions associated with increased oxidative stress. PUBLIC HEALTH RELEVANCE: We have shown that alpha-tocopherol is the most potent vitamin E form because the human body actively regulates its plasma concentrations and delivery to tissues while other vitamin E forms are actively metabolized and excreted. The proposed studies will use optimized methods for pharmacokinetic measurements and apply these to the problem of assessing "how much vitamin E is needed by the body?", and do these needs change with increased oxidative stress or decreased vitamin C status.