Prenatal Conditions and the Pathway to Obesity and Diabetes in Children

描述（由申请人提供）：先兆子痫（PE）与母亲和儿童患糖尿病（DM）的风险增加相关。同样，妊娠期糖尿病女性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成问题，她们患T2 DM和PE的风险要高得多，肯定会导致西班牙裔和美国印第安人青年中T2 DM问题日益严重。总体假设是，母体DM和PE的影响结合联合收割机，通过表观遗传机制改变基因表达和改变循环因子，使后代患DM/MS的风险增加。这有效地“程序”后代为以后的DM/MS。为了测试这一点，选定的后代与DM和高风险的PE孕妇将研究从出生到4岁。第一个目的是检查母体T2 DM单独和并发PE对生长、身体组成和代谢指标的影响。通过双能X线吸收法和磁共振成像评估身体成分，沿着获得标准人体测量指标。沿着代谢率的测量，测定血清葡萄糖、胰岛素和脂质浓度。第二个目的是检验以下假设：DM母亲（PE）出生的婴儿在出生前暴露于细胞因子/炎症因子的库，导致不利的代谢指标和身体组成。第三个目标是绘制表观遗传修饰图，以确定相关的靶基因。HELP检测用于鉴定胎盘和白细胞DNA中特定遗传基因座的胞嘧啶甲基化变异。明确未来糖尿病的发病机制、危险因素和替代标志物可以为预防高危人群糖尿病提供新的途径。 公共卫生相关性：儿童肥胖症正以惊人的速度增长，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。这个项目研究了易患肥胖和糖尿病的母亲因素，以及它们如何影响学龄前儿童。这些信息将有助于设计具体的干预措施和评估其效力。

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.