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、代谢综合征和后来的心血管疾病(CVD)的独立危险因素。肥胖儿童(BMI第95百分位数)和超重儿童(BMI第85-94百分位数)表现出心血管疾病危险因素和维生素D缺乏症的相对较高患病率，他们的动脉粥样硬化风险从儿童到成年。因此，在维生素D缺乏的肥胖和超重儿童中补充维生素D有可能改善他们的心脏代谢健康，降低他们日后患心血管疾病的风险。在这项提案中，我们将检验中心假设，即增强维生素D状态将改善这些儿童的血管健康以及他们的心血管疾病和代谢综合征风险概况。我们的主要目标是在10至18岁的肥胖和超重儿童中确定维生素D缺乏(定义为血清25-羟基维生素D&lt；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有效性；并评估这些影响是否具有剂量依赖性。作为第二个目标，我们将检查维生素D补充剂对脂肪因子和与心血管疾病风险相关的炎症标记物的影响。在一项双盲对照试验中，我们将随机选择252名符合条件的儿童，让他们在6个月内每天接受600IU(常规补充剂)、1000IU或2000IU(强化补充剂)维生素D3。在基线、3个月和6个月时评估的研究结果指标将包括：(1)作为血管内皮功能指标的臂动脉血流介导的扩张(FMD)；(2)作为动脉僵硬指标的脉搏波速度；(3)胰岛素敏感性的替代估计(空腹血糖/空腹胰岛素比率或胰岛素抵抗评估的稳态模型[HOMA-IR])；(4)代谢综合征危险因素(血压、腰围、高密度脂蛋白、甘油三酯和空腹血糖)；(5)炎症标志物(如CRP、IL-6、TNF-α)；(6)脂肪因子(瘦素和脂联素)；和(7)一氧化氮代谢产物。6个月时的腕部FMD将是主要的结果衡量标准。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强化维生素D3补充剂的安全性。体脂总量将通过双能X射线吸收测量法确定，以检查肥胖对结果测量的混杂影响。这项建议的创新方面包括(1)表征血管健康和心脏代谢风险结果的时间变化，以响应血管功能障碍和心脏代谢风险高危儿童中维生素D状况的提高；以及(2)描绘维生素D对与心血管疾病风险相关的炎症标记物和脂肪因子的影响。确定维生素D的保护益处将具有重大的公共卫生意义，因为优化维生素D状况将是改善儿童心脏代谢健康和降低成年期间心血管疾病风险的一种廉价的初级预防策略。

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.