Phytoestrogens, insulin resistance and endothelial function

植物雌激素、胰岛素抵抗和内皮功能

基本信息

批准号：
8174263
负责人：
NINA STACHENFELD
金额：
$ 23.87万
依托单位：
JOHN B. PIERCE LABORATORY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8174263
关键词：
Affinity Age Attenuated Binding Biological Availability Blood Circulation Blood Vessels Blood flow Cardiovascular Physiology Cardiovascular system Chronic Cutaneous Data Data Protection Diabetes Mellitus Disease Dose Endothelium Estradiol Estrogen Receptors Estrogen Therapy Estrogens Exposure to Future Genistein Goals Hormone replacement therapy Hormones Human Hypertension Individual Infusion procedures Insulin Insulin Resistance Laser-Doppler Flowmetry Measures Mediating Metabolic Microcirculation Microdialysis Modeling Nitric Oxide Obesity Organ Pathway interactions Peripheral Pharmaceutical Preparations Physicians Phytoestrogens Plants Play Public Health Regulation Relaxation Reporting Risk Factors Role Skin Soy Proteins Soybeans Symptoms Systemic disease Testing Uncertainty Vascular resistance Vasodilation Vasomotor Woman Women&apos s Group alternative treatment base cancer risk cardiovascular disorder risk design glucose disposal improved malignant breast neoplasm minimally invasive older men older women receptor reproductive response soy vascular bed

项目摘要

DESCRIPTION (provided by applicant): With the goal of reducing the age-associated vasomotor symptoms and decreasing the risk of cardiovascular disease, many women choose over the counter phytoestrogens in favor of estrogens prescribed by their physicians. Genistein is the best studied and most common of the soy-derived phytoestrogens. Genistein is structurally similar to 172-estradiol and has high affinity for the ER2 receptor present in the human vasculature, but low affinity for the ER1 receptor present in reproductive organs. Studies support beneficial effects of soy-derived phytoestrogens on vascular reactivity and endothelial function. However, during genistein treatment the expected improvement in endothelial dependent dilation is attenuated in individuals with insulin resistance. This project is designed to study the impact of genistein on microvascular reactivity both in healthy women and in women with insulin resistance. Our general hypothesis is that genistein improves endothelial function through a nitric oxide mechanism in healthy women, but that this mechanism is ineffective in women with insulin resistance. We will use the cutaneous vasculature as a model to study endothelial function, and will infuse estradiol and genistein directly into the skin using microdialysis while measuring microvascular blood flow with laser Doppler flowmetry. Our first Aim will use dose-response curves to determine the 172-estradiol and genistein effects on the peripheral microvasculature in women with and without insulin resistance. We hypothesize that both hormone infusions will increase blood flow in both groups of women, but the vasodilation will be attenuated in women with insulin resistance. Our second Aim tests the hypothesis that nitric oxide mediates the estradiol and genistein-induced vasodilation in healthy women, but is not a factor in the more moderate vasodilation seen in women with insulin resistance. Women take genistein and other phytoestrogens assuming a level of cardiovascular protection, but data have not definitively demonstrated these benefits. Our studies will directly assess the extent to which genistein impacts vasodilation and examine the mechanism for its effects. Moreover, our findings will provide a basis to study the impact of genistein and other phytoestrogens on other conditions associated with compromised peripheral circulation such as Reynaud's disease and hypertension. The proposed studies will not only provide mechanistic information on the interaction between estradiol, genistein, insulin resistance and endothelial function, but will serve as a basis for future studies in older women and men with insulin resistance. PUBLIC HEALTH RELEVANCE: With the goal of reducing vasomotor symptoms and protection against the age-associated increase in cardiovascular disease risk, women are increasingly choosing over the counter phytoestrogens (such as genistein) in favor of estrogens prescribed by their physicians. Genistein may improve vascular function but not carry with it the increased breast cancer risks that have been associated with estrogen exposure. Insulin resistance increases cardiovascular disease risk, and may also interfere with the actions of genistein on cardiovascular function. Therefore, these studies have broad public health implications because it is important that women not have a false sense of cardiovascular protection while taking genistein.

描述（由申请人提供）：为了减少与年龄相关的血管舒缩症状并降低心血管疾病的风险，许多女性选择非处方植物雌激素，而不是医生开出的雌激素。金雀异黄酮是研究最深入、最常见的大豆来源植物雌激素。金雀异黄素在结构上与 172-雌二醇相似，对人类脉管系统中存在的 ER2 受体具有高亲和力，但对生殖器官中存在的 ER1 受体具有低亲和力。研究支持大豆来源的植物雌激素对血管反应性和内皮功能的有益作用。然而，在金雀异黄素治疗期间，对于具有胰岛素抵抗的个体，内皮依赖性扩张的预期改善会减弱。该项目旨在研究金雀异黄素对健康女性和胰岛素抵抗女性微血管反应性的影响。我们的一般假设是金雀异黄素通过一氧化氮机制改善健康女性的内皮功能，但这种机制对胰岛素抵抗的女性无效。我们将使用皮肤脉管系统作为模型来研究内皮功能，并使用微透析将雌二醇和染料木黄酮直接注入皮肤，同时使用激光多普勒血流计测量微血管血流量。我们的第一个目标将使用剂量反应曲线来确定 172-雌二醇和染料木黄酮对有或没有胰岛素抵抗的女性外周微血管的影响。我们假设两种激素输注都会增加两组女性的血流量，但在患有胰岛素抵抗的女性中，血管舒张作用会减弱。我们的第二个目标测试了这样的假设：一氧化氮介导健康女性中雌二醇和金雀异黄素诱导的血管舒张，但不是胰岛素抵抗女性中所见的较中度血管舒张的因素。女性服用金雀异黄酮和其他植物雌激素可以起到一定程度的心血管保护作用，但数据尚未明确证明这些益处。我们的研究将直接评估金雀异黄素影响血管舒张的程度并检查其作用机制。此外，我们的研究结果将为研究金雀异黄酮和其他植物雌激素对与外周循环受损相关的其他疾病（如雷诺氏病和高血压）的影响提供基础。拟议的研究不仅将提供雌二醇、金雀异黄素、胰岛素抵抗和内皮功能之间相互作用的机制信息，还将作为未来对患有胰岛素抵抗的老年女性和男性的研究的基础。公共健康相关性：为了减少血管舒缩症状并防止与年龄相关的心血管疾病风险增加，女性越来越多地选择非处方植物雌激素（例如染料木黄酮），而不是医生开出的雌激素。金雀异黄素可以改善血管功能，但不会增加与雌激素暴露相关的乳腺癌风险。胰岛素抵抗会增加心血管疾病的风险，也可能干扰金雀异黄素对心血管功能的作用。因此，这些研究具有广泛的公共卫生意义，因为女性在服用金雀异黄酮时不要产生心血管保护的错误观念，这一点很重要。