Preeclampsia and fetal origins of childhood insulin resistance, risk for type 2 d

描述（由申请人提供）：流行病学研究表明，宫内发育迟缓（IUGR）与成年期不良代谢结局相关，如肥胖、2型糖尿病和心血管疾病。子痫前期（PE）是一种具有代谢综合征许多特征的异质性疾病，众所周知与胎儿尺寸减小有关。目前尚不清楚PE妊娠的小于胎龄儿（SGA）后代患成人发病疾病的风险是否与非PE妊娠的SGA相同或更高。胰岛素抵抗被认为是IUGR与2型糖尿病（T2 DM）和心血管疾病（CVD）风险相关的主要病理生理机制。目前的研究是一项试点和可行性研究，旨在调查PE与非PE妊娠导致的IUGR与作为成人疾病前因的儿童代谢标志物的关系。为此，我们将比较儿童（年龄8-17岁），他们是患有PE的母亲与没有PE的母亲的SGA（出生体重低于第10百分位数）后代，这些儿童已经作为NIH资助的赠款“产前暴露和先兆子痫预防（PEPP）”的一部分进行了随访。这是一项正在进行的研究，在Magee妇女医院，PI博士詹姆斯·罗伯茨，我们的赠款合作者，有超过2900名妇女参加自1993年成立以来。该R 03试点可行性提交文件旨在：1）优化PEPP女性后代的招募工作; 2）启动代谢研究，以解决我们的假设并为R 01提案开发初步数据。我们假设与非PE妊娠的SGA儿童和与阿加儿童相比，继发于先兆子痫的SGA儿童有1）全身和腹部肥胖增加，2）胰岛素敏感性和分泌受损，3）更差的心血管疾病风险特征和4）更差的功能性肾上腺高雄激素血症。除了口服葡萄糖耐量试验以评估葡萄糖耐量外，还将通过DEXA仔细评价全身肥胖、通过计算机断层扫描仔细评价内脏和皮下腹部脂肪组织、通过高胰岛素血症-正常血糖和高血糖钳夹的金标准仔细评价心血管疾病风险特征、胰岛素敏感性和胰岛素分泌来检验这些假设。将通过促肾上腺皮质激素刺激试验评估肾上腺高雄激素血症。对这一性质的全面评估将有助于梳理出PE与其他子宫内不良事件对代谢风险和未来成人疾病的风险是否有差异性增加。这一领域的研究对于确定宫内环境对儿童期风险因素的影响至关重要，这些风险因素是未来胰岛素抵抗及其并发症（包括肥胖、T2 DM和CVD）发展的基础。从这项研究计划中获得的信息将构成我们未来研究子痫前期与其他宫内事件程序儿童和成人疾病风险因素的机制的基石。

DESCRIPTION (provided by applicant): Epidemiological studies have demonstrated that intrauterine growth retardation (IUGR) is associated with adverse metabolic outcomes in adulthood such as obesity, type 2 diabetes, and cardiovascular disease. Preeclampsia (PE), a heterogeneous condition with many features of the metabolic syndrome, is well known to be associated with reduced fetal size. It is not clear if small for gestational age (SGA) offspring of PE pregnancies are at the same or higher risk for adult-onset disease than SGA from non PE pregnancies. Insulin resistance is proposed to be the main culprit as an underlying pathophysiological mechanism linking IUGR and risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD). The current study is a pilot and feasibility study that aims to investigate the relationship of IUGR resulting from PE vs. non PE pregnancies, to childhood metabolic markers as antecedents of adult disease. To that effect, we will compare children (ages 8-17 yrs) who were SGA (birth weight less than 10th percentile) offspring of mothers with vs. without PE who have been followed as part of the NIH funded grant "Prenatal Exposure and Preeclampsia Prevention (PEPP)". This is an on-going study at Magee Womens Hospital, PI Dr. James Roberts, a collaborator on our grant, with over 2900 women enrolled since its inception in 1993. This R03 pilot feasibility submission is to: 1) optimize recruitment efforts of the offspring of the PEPP women; and 2) initiate the metabolic studies which address our hypotheses and develop preliminary data for an R01 proposal. We hypothesize that children born SGA secondary to preeclampsia have 1) increased total body and abdominal adiposity, 2) impaired insulin sensitivity and secretion, 3) worse cardiovascular disease risk profile and 4) worse functional adrenal hyperandrogenism compared with SGA children from non PE pregnancies and compared with AGA children. These hypotheses will be tested by careful evaluation of total body adiposity by DEXA, visceral and subcutaneous abdominal adipose tissue by computed tomography scan, cardiovascular disease risk profile, insulin sensitivity and insulin secretion by the gold standard of the hyperinsulinemic- euglycemic and hyperglycemic clamps, in addition to the oral glucose tolerance test to assess glucose tolerance. Adrenal hyperandrogenism will be assessed by adrenocorticotropin hormone stimulation test. A comprehensive evaluation of this nature will help tease out whether there is a differentially increased risk of PE vs. other adverse in utero events on metabolic risk and future adult disease. Research in this area is imperative to determine the effect of the intrauterine environment on childhood risk factors underlying the future development of insulin resistance and its complications including obesity, T2DM and CVD. The information obtained from this research proposal will constitute the building blocks for our future investigations of the mechanisms by which preeclampsia vs. other in-utero events program childhood and adult disease risk factors.