Phytoestrogens, insulin resistance and endothelial function

植物雌激素、胰岛素抵抗和内皮功能

• 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
• 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' 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

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，许多妇女选择在柜台植物雌激素上选择对医生开具的雌激素的选择。染料木黄酮是最经过研究，最常见的大豆衍生的植物雌激素。染料木黄酮在结构上与172-雌二醇相似，并且对存在于人类脉管系统中的ER2受体具有高亲和力，但对生殖器官中存在的ER1受体的亲和力较低。研究支持大豆衍生的植物雌激素对血管反应性和内皮功能的有益作用。然而，在染料木黄酮治疗期间，胰岛素抵抗的个体会减弱内皮依赖性扩张的预期改善。该项目旨在研究健康女性和胰岛素抵抗女性微血管反应性的影响。我们的总体假设是，染料木黄酮通过健康女性的一氧化氮机制改善内皮功能，但是这种机制在胰岛素抵抗的女性中无效。我们将使用皮肤脉管系统作为研究内皮功能的模型，并使用微透析直接将雌二醇和染料木黄酮直接注入皮肤中，同时用激光多普勒流动仪测量微血管血流。我们的第一个目标将使用剂量反应曲线来确定有或没有胰岛素抵抗性的女性的172-雌二醇和染料木黄酮对外围微脉管系统的影响。我们假设两组女性的两种激素输注都会增加血液的血流，但是在具有胰岛素抵抗的女性中，血管舒张会减弱。我们的第二个目标检验了以下假设：一氧化氮介导雌性女性的雌二醇和染料黄酮诱导的血管舒张，但不是胰岛素抵抗女性中更为中度血管舒张的因素。妇女假设具有一定程度的心血管保护，但妇女服用染料木黄酮和其他植物雌激素，但数据尚未明确证明这些好处。我们的研究将直接评估染料木黄酮影响血管舒张的程度，并检查其作用的机制。此外，我们的发现将提供一个基础，以研究染料木黄酮和其他植物雌激素对与雷诺氏病和高血压等受损外周循环有关的其他疾病的影响。拟议的研究不仅将提供有关雌二醇，染料木黄酮，胰岛素抵抗和内皮功能之间相互作用的机械信息，而且还将作为对具有胰岛素抵抗的老年男性和男性的未来研究的基础。 公共卫生相关性：为了减少血管舒适症状并防止与年龄相关的心血管疾病风险增加，妇女越来越多地选择反植物雌激素（例如Genastein），以支持其医生规定的雌激素。染料木黄酮可能改善血管功能，但不能随身携带与雌激素暴露有关的乳腺癌风险增加。胰岛素抵抗会增加心血管疾病的风险，也可能干扰染料木黄酮对心血管功能的作用。因此，这些研究具有广泛的公共卫生影响，因为重要的是，女性在服用染料木黄酮时没有错误的心血管保护感。