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，妊娠期糖尿病妇女的后代患糖尿病和代谢综合征（MS）的风险也会增加。这在美洲印第安人和西班牙裔妇女中尤其成问题，她们患2型糖尿病和PE的风险要高得多，这肯定会导致西班牙裔和美洲印第安青年患2型糖尿病的问题日益严重。总体假设是，母体糖尿病和PE的影响通过表观遗传机制改变基因表达和改变循环因子，从而增加了后代患DM/MS的风险。这有效地“编程”了后代，以适应后来的DM/MS。为了验证这一点，选择患有糖尿病和PE高风险的孕妇的后代从出生到4岁进行研究。第一个目的是研究母亲单独T2DM和合并PE对生长、身体组成和代谢指标的影响。通过双能x射线吸收仪和磁共振成像对人体成分进行评估，并获得标准的人体测量值。测定血清葡萄糖、胰岛素和脂质浓度，同时测定代谢率。第二个目的是验证一个假设，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，导致不利的代谢指数和身体组成。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测定用于鉴定胎盘和白细胞DNA中特定遗传位点的胞嘧啶甲基化变异。明确未来糖尿病的机制、危险因素和替代标志物可以为高危人群预防糖尿病提供新的途径。

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.