Prenatal Conditions and the Pathway to Obesity and Diabetes in Children

描述(由申请人提供)：先兆子痫(PE)与母亲和孩子患糖尿病(DM)的风险增加有关。同样，怀孕期间患有糖尿病的妇女的后代患糖尿病和代谢综合征(MS)的风险也会增加。这在美国印第安人和西班牙裔女性中尤其严重，她们患T2 DM和PE的风险要高得多，这肯定会导致西班牙裔和美国印第安人青年中日益严重的T2 DM问题。最重要的假设是，母体DM和PE的影响通过表观遗传机制改变基因表达和改变循环因素，共同增加了子代DM/MS的风险。这有效地为以后的糖尿病/多发性硬化的后代“编程”。为了测试这一点，选择患有糖尿病和PE高危孕妇的后代将从出生到4岁进行研究。第一个目的是研究母亲单独的T2 DM和合并PE对生长、身体成分和代谢指标的影响。通过双能X射线吸收测量和磁共振成像，获得标准的人体测量以及身体成分的评估。测定血糖、胰岛素和血脂浓度，同时测量代谢率。第二个目的是检验这样一种假设，即糖尿病母亲(PE)所生的婴儿在出生前暴露于一系列细胞因子/炎症因子，从而导致不利的代谢指数和身体成分。第三个目的是定位表观遗传修饰，以确定相关的靶基因。HELP分析用于鉴定胎盘和白细胞DNA中特定遗传位点上胞嘧啶甲基化的变异。明确未来糖尿病的机制、危险因素和替代标记物可以引导在高危人群中预防糖尿病的新方法。 与公共健康相关：儿童肥胖率正在以惊人的速度增长，并威胁着他们未来的健康，特别是在美国印第安人和西班牙裔美国人中。这个项目调查了易患肥胖症和糖尿病的母体因素以及它们对学龄前儿童的影响。这些信息将有助于设计具体的干预措施并评估其有效性。

DESCRIPTION (provided by applicant): Pre-eclampsia (PE) is associated with an increased risk for diabetes mellitus (DM) for both mother and child. Similarly, the risk for DM and metabolic syndrome (MS) is increased for the offspring of women with DM during pregnancy. This is especially problematic among American Indian and Hispanic women who are at much higher risk for T2DM and PE and surely contributes to the growing problem of T2DM in Hispanic and American Indian youth. The overarching hypothesis is that the effects of maternal DM and PE combine to compound the risk of DM/MS in offspring by changing gene expression via epigenetic mechanisms and altering circulating factors. This effectively "programs" the offspring for later DM/MS. To test this, selected offspring of pregnant women with DM and at high risk for PE will be studied from birth to age 4 years. The first aim examines the effect of maternal T2DM alone and complicated by PE on growth, body composition, and metabolic indices. Standard anthropometric measures are obtained along with assessment of body composition by dual energy X-ray absorptiometry and magnetic resonance imaging. Serum glucose, insulin and lipid concentrations are determined along with measures of metabolic rate. The second aim tests the hypothesis that an infant born to DM mother ( PE) is exposed to repertoire of cytokines/inflammatory factors before birth that leads to unfavorable metabolic indices and body composition. The third aim maps epigenetic modifications in order to identify relevant target genes. The HELP assay is employed to identify variation in cytosine methylation at specific genetic loci in placental and leukocyte DNA. Defining the mechanisms, risk factors, and surrogate markers of future DM can lead new ways to prevent DM in high risk populations. PUBLIC HEALTH RELEVANCE: Obesity is increasing at an alarming rate in children and threatening their future health, especially among American Indians and Hispanics. This project examines the maternal factors that predispose to obesity and diabetes and how they affect preschool-aged children. This information will be useful in designing specific interventions and assessing their efficacy.