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，宫内生长迟缓（IUGR）与成年期不良代谢结局（如肥胖、2型糖尿病和心血管疾病）相关。先兆子痫（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妊娠的小胎龄（SGA）后代与非PE妊娠的小胎龄（SGA）后代患成人发病疾病的风险是否相同或更高。胰岛素抵抗被认为是IUGR与2型糖尿病（T2DM）和心血管疾病（CVD）风险相关的潜在病理生理机制的罪魁祸首。目前的研究是一项试点和可行性研究，旨在调查妊娠PE和非妊娠PE导致的IUGR与儿童代谢标志物作为成人疾病的前兆之间的关系。为此，我们将比较作为NIH资助的“产前暴露和先兆子痫预防（pep）”的一部分跟踪研究的PE母亲与非PE母亲的SGA（出生体重低于10%）后代的儿童（8-17岁）。这是一项正在Magee女子医院进行的研究，James Roberts博士是我们资助的合作者，自1993年开始以来，已有2900多名妇女参加了这项研究。本R03试点可行性报告旨在：1)优化PEPP女性后代的招募努力；2)启动代谢研究，以解决我们的假设，并为R01提案提供初步数据。我们假设继发于子痫前期的SGA患儿有：1)全身和腹部脂肪增加；2)胰岛素敏感性和分泌受损；3)心血管疾病风险更严重；4)与非PE妊娠的SGA患儿和AGA患儿相比，肾上腺功能高雄激素症更严重。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，心血管疾病风险分析，胰岛素敏感性和胰岛素分泌（高胰岛素-正血糖和高血糖钳的金标准），以及口服葡萄糖耐量试验来评估葡萄糖耐量。肾上腺高雄激素症将通过促肾上腺皮质激素刺激试验进行评估。对这种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在代谢风险和未来成人疾病方面是否存在差异增加的风险。这一领域的研究对于确定宫内环境对儿童时期胰岛素抵抗及其并发症（包括肥胖、2型糖尿病和心血管疾病）发展的潜在危险因素的影响是必要的。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.