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

描述(申请人提供)：流行病学研究表明，胎儿宫内发育迟缓(IUGR)与成年后的不良代谢结果有关，如肥胖、2型糖尿病和心血管疾病。子痫前期(PE)是一种具有许多代谢综合征特征的异质性疾病，众所周知，它与胎儿尺寸缩小有关。目前尚不清楚PE妊娠的小于胎龄儿(SGA)患成人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)风险之间联系的一个潜在的病理生理机制。目前的研究是一项先导性和可行性研究，旨在调查PE和非PE妊娠引起的IUGR与儿童代谢标志物之间的关系，作为成人疾病的前驱因素。为此，我们将比较患有PE的母亲和没有PE的母亲所生的SGA(出生体重低于10%)儿童(8-17岁)与没有PE的母亲的孩子，后者一直被作为NIH资助的赠款的一部分进行跟踪调查，该基金的资助名为“产前暴露和先兆子痫预防(Pepp)”。这是玛吉妇女医院正在进行的一项研究，詹姆斯·罗伯茨博士是我们赠款的合作者之一，自1993年开始以来，有2900多名妇女参加了这项研究。这份R03试点可行性意见书是：1)优化PEPP女性后代的招募工作；2)启动代谢研究，解决我们的假设，并为R01提案开发初步数据。我们假设，与非PE妊娠的SGA儿童和AGA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)心血管疾病风险更差，4)功能性肾上腺高雄激素血症更严重。这些假设将通过DEXA对全身脂肪的仔细评估，通过计算机断层扫描对内脏和皮下腹部脂肪组织的评估，心血管疾病风险概况，胰岛素敏感性和以高胰岛素-正常血糖和高血糖钳夹为金标准的胰岛素分泌，以及评估葡萄糖耐量的口服葡萄糖耐量试验来验证。肾上腺高雄激素血症将通过促肾上腺皮质激素刺激试验进行评估。对这一性质的全面评估将有助于梳理出在代谢风险和未来成人疾病方面，PE与其他宫内不良事件的风险是否存在不同程度的增加。这一领域的研究势在必行，以确定宫内环境对儿童胰岛素抵抗及其并发症(包括肥胖、T2 DM和心血管疾病)未来发展的潜在危险因素的影响。从这项研究提案中获得的信息将构成我们未来研究先兆子痫与其他宫内事件规划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.