Estrogen-Mediated Impairments of Vascular Health in Diabetes

糖尿病最近被称为“21世纪世纪的流行病”，并导致了严重的疾病。 对美国公共卫生造成经济负担。心血管疾病（CVD）占80%， 糖尿病的发病率和死亡率，然而，女性1型糖尿病患者有更大的风险， CVD与糖尿病男性相比。理解CVD风险中的性别二态性的关键障碍是 缺乏关于雌激素（E2）对糖尿病女性血管健康作用的知识。氧化 应激是糖尿病患者中常见的表型， 糖尿病并发症此外，sirtuin 1（Sirt 1）被认为在调节细胞凋亡中起着重要作用。 一氧化氮（NO）的生物利用度，并且在糖尿病患者中较低。因此，我们的中心假设是 女性1型糖尿病患者E2浓度升高有助于NO- 生物利用度和血管健康通过两个独立的途径;增加氧化应激和 减少循环Sirt 1。作为佐证，令人信服的初步数据表明， 从月经到月经周期的卵泡晚期的血管健康在1型糖尿病的存在下丧失， 糖尿病此外，这种损失与氧化应激增加和Sirt 1降低有关。探讨 E2对糖尿病女性血管健康的影响，我们建议利用月经周期作为一种自然的 以及研究性类固醇激素变化的新方法。我们将进行全面的 评估男性血管健康和绝经前月经周期中两个不同时间的血管健康 患有和不患有1型糖尿病的女性：1）月经期间（低雌激素/低孕激素）和2）晚期 卵泡期（升高的雌激素/低孕酮）。此外，我们将采用两种新的治疗方法， 可能会降低糖尿病患者未来的CVD风险。研究结果不仅有助于了解 与糖尿病CVD风险性别差异相关的分子机制，他们可能会发现新的 降低女性糖尿病患者雌激素介导的血管功能障碍的治疗方法。这 该提案展示了翻译研究的真实模式，代表了方法的重大转变 了解1型糖尿病患者心血管疾病风险的性别差异。

Diabetes has recently been referred to as “the epidemic of the 21st century” and contributes to a substantial economic burden on the United States public health. Cardiovascular disease (CVD) accounts for 80% of morbidity and mortality in diabetes, however, women with type 1 diabetes have a substantially greater risk for CVD compared to men with diabetes. A critical barrier to understanding this sexual dimorphism in CVD risk is the lack of knowledge regarding the role of estrogen (E2) on vascular health in diabetic women. Oxidative stress is a common phenotype in patients with diabetes and is routinley associated with hyperglycemia and diabetic complications. In addition, sirtuin1 (Sirt1) has been proposed to play a fundemental role in regulating nitric oxide (NO) bioavailability, and is lower in patients with diabetes. Accordingly, our central hypothesis is that an elevated concentration of E2 in women with type 1 diabetes contributes to a reduction in NO- bioavailability and vascular health through two separate pathways; an increase in oxidative stress and a decrease in circulating Sirt1. In support, compelling preliminary data indicate that the natural increase in vascular health from menses to the late follicular phase of the menstrual cycle is lost in the presence of type 1 diabetes. In addition, this loss is associated with increased oxidative stress and lower Sirt1. To investigate the impact of E2 on vascular health in women with diabetes, we propose to utilize the menstrual cycle as a natural and novel method to investigate changes in sex-steroid hormones. We will perform a comprehensive assessment of vascular health in men and at two different times during the menstrual cycle in premenopausal women with and without type 1 diabetes: 1) during the menses (low estrogen/low progesterone) and 2) late follicular (elevated estrogen/low progesterone) phases. In addition, we will employ two novel treatments that may mitigate future CVD risk in patients with diabetes. Findings will not only contribute to understanding the molecular mechanisms associated with sex disparities of CVD risk in diabetes, they may identify novel therapeutic approaches to decrease estrogen-mediated vascular dysfunction in women with diabetes. This proposal demonstrates the true model of translational research and represents a major shift in the approach to understanding the sexual dimorphism of CVD risk in patients with type 1 diabetes.