Vitamin D and Vascular Function in Obese Children

描述（由申请人提供）：维生素D缺乏正在成为儿童亚临床血管功能障碍、代谢综合征和后期心血管疾病（CVD）的独立危险因素。肥胖儿童（BMI第95百分位）和超重儿童（BMI第85 -94百分位）表现出心血管疾病的危险因素和相对较高的维生素D缺乏症患病率，他们的动脉粥样硬化风险从童年到成年都有追踪。因此，维生素D缺乏的肥胖和超重儿童补充维生素D有可能改善他们的心脏代谢健康，降低他们以后患心血管疾病的风险。在这一提议中，我们将测试中心假设，即增强这些儿童的维生素D水平将改善他们的血管健康和心血管疾病和代谢综合征的风险。我们的主要目的是确定10至18岁的肥胖和超重儿童维生素D缺乏症（定义为血清25-羟基维生素D <20 ng/mL），增强维生素D3补充在改善血管内皮功能、动脉僵硬、胰岛素敏感性和代谢综合征风险状态方面的功效；并评估这些效应是否有剂量依赖性。作为次要目标，我们将研究维生素D补充剂对与心血管疾病风险相关的脂肪因子和炎症标志物的影响。在一项双盲对照试验中，我们将随机选取252名符合条件的儿童，每天服用600 IU（常规补充）、1000 IU或2000 IU（强化补充）维生素D3，持续6个月。在基线、3个月和6个月时评估的研究结果测量将包括：(1)肱动脉血流介导的扩张（FMD）作为血管内皮功能的测量；(2)脉搏波速作为衡量动脉刚度的指标；(3)胰岛素敏感性的替代评估（空腹血糖/空腹胰岛素比率或胰岛素抵抗稳态评估模型[HOMA-IR]）；(4)代谢综合征危险因素（血压、腰围、高密度脂蛋白胆固醇、甘油三酯、空腹血糖）；(5)炎症标志物（如CRP、IL-6、tnf - α）；(6)脂肪因子（瘦素和脂联素）；(7)一氧化氮代谢物。6个月时的肱口蹄疫将是主要的结局指标。我们将在3个月和6个月的随访中通过测量血清钙来评估增强维生素D3补充的安全性。将通过双能x线吸收仪确定全身脂肪，以检查肥胖对结果测量的混杂影响。该建议的创新方面包括：(1)在血管功能障碍和心脏代谢风险高风险的儿童人群中，描述维生素D水平提高对血管健康和心脏代谢风险结果的时间变化的响应；(2)阐明维生素D对与心血管疾病风险相关的炎症标志物和脂肪因子的影响。确定维生素D的保护作用具有重要的公共卫生意义，因为优化维生素D状态将是改善儿童时期心脏代谢健康和降低成年期心血管疾病风险的廉价初级预防策略。

DESCRIPTION (provided by applicant): Vitamin D deficiency is emerging as an independent risk factor for subclinical vascular dysfunction, metabolic syndrome, and later cardiovascular disease (CVD) in children. Obese children (BMI 95th percentile) and overweight children (BMI 85th-94th percentile) exhibit CVD risk factors and a relatively high prevalence of hypovitaminosis D, and their atherogenic risks track from childhood to adulthood. Therefore, vitamin D replenishment in vitamin D-deficient obese and overweight children has the potential to improve their cardiometabolic health and reduce their risk of CVD later in life. In this proposa, we will test the central hypothesis that enhancement of vitamin D status in such children will improve their vascular health and their CVD and metabolic syndrome risk profile. Our primary objective is to determine, in obese and overweight children aged 10 to 18 years with vitamin D deficiency (defined as serum 25-hydroxyvitamin D <20 ng/mL), the efficacy of enhanced vitamin D3 supplementation in improving vascular endothelial function, arterial stiffness, insulin sensitivity, and metabolic syndrome risk status; and to assess whether these effects are dose- dependent. As a secondary objective, we will examine the vitamin D supplementation-induced effect on adipokines and inflammatory markers relevant to CVD risk. In a double-masked, controlled trial, we will randomize 252 eligible children to receive either 600 IU (conventional supplementation), or 1000 IU or 2000 IU (enhanced supplementation) of vitamin D3 daily for 6 months. Study outcome measures, assessed at baseline, 3 and 6 months, will include (1) brachial artery flow-mediated dilation (FMD) as a measure of vascular endothelial function; (2) pulse wave velocity as a measure of arterial stiffness; (3) surrogate estimates of insulin sensitivity (fasting glucose/fasting insulin ratio or Homeostasis Model of Assessment - Insulin Resistance [HOMA-IR]); (4) metabolic syndrome risk factors (blood pressure, waist circumference, HDL cholesterol, triglycerides, and fasting blood glucose); (5) inflammatory markers (e.g. CRP, IL-6, TNF-alpha); (6) adipokines (leptin and adiponectin); and (7) nitric oxide metabolites. Brachial FMD at 6 months will be the primary outcome measure. We will assess the safety of enhanced vitamin D3 supplementation by measuring serum calcium at the 3- and 6-month-follow-ups. Total body fat will be ascertained by Dual-energy X-ray Absorptiometry to examine the confounding effects of adiposity on outcome measures. Innovative aspects of this proposal include (1) characterizing the temporal changes in vascular health and cardiometabolic risk outcomes in response to enhancement of vitamin D status in a population of children at high-risk for vascular dysfunction and cardiometabolic risks; and (2) delineating the vitamin D effects on inflammatory markers and adipokines relevant to CVD risk. Establishing the protective benefits of vitamin D would have major public health importance, since optimization of vitamin D status would be an inexpensive primary prevention strategy for improving cardiometabolic health during childhood and for reducing CVD risk during adulthood.