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

先兆子痫和儿童期胰岛素抵抗的胎儿起源、2 型风险

• 批准号: 8412853
• 负责人: FIDA BACHA
• 金额: $ 6.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412853
• 关键词: Preeclampsia; fetal; origins; childhood; insulin; Preeclampsia; fetal; origins; childhood; insulin

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.

描述（由申请人提供）：流行病学研究表明，宫内内生长迟缓（IUGR）与肥胖，2型糖尿病和心血管疾病等成年后的不良代谢结果有关。子痫前期（PE）是一种具有代谢综合征许多特征的异质疾病，众所周知与胎儿大小减少有关。目前尚不清楚PE妊娠的胎龄（SGA）后代是否比非PE妊娠的SGA相同或更高的成人疾病风险。胰岛素抵抗被认为是主要的罪魁祸首，是一种联系IUGR和2型糖尿病（T2DM）和心血管疾病（CVD）风险的基本病理生理机制。当前的研究是一项试点和可行性研究，旨在研究由PE与非PE妊娠引起的IUGR与童年代谢标记作为成人疾病的前因的关系。为此，我们将比较SGA的儿童（8-17岁）的儿童（出生体重小于10％）的后代与没有PE的母亲的儿童，他们是NIH资助的赠款“产前暴露和预倾向于预防先前的预防率（PEPP）的一部分”。这是Magee Womens Hospital的一项正在进行的研究，PI詹姆斯·罗伯茨（Pi James Roberts）博士是我们赠款的合作者，自1993年成立以来，有2900多名妇女入学。此R03飞行员的可行性提交是：1）优化Pepp妇女后代的招聘工作； 2）启动代谢研究，以解决我们的假设并为R01提案开发初步数据。我们假设继发于先兆子痫的SGA的儿童具有1）胰岛素敏感性和分泌受损的总体和腹部肥胖，3）较差的心血管疾病风险和4）功能性肾上腺超女生与非PE妊娠的SGA儿童相比，与AGA儿童相比，功能较差。 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 宽容。肾上腺过度雄激素将通过肾上腺皮质激素刺激试验评估。对这种性质的全面评估将有助于弄清楚在代谢风险和未来成人疾病的子宫内事件中，PE的风险是否有差异化的风险。在这一领域的研究必须确定宫内环境对胰岛素抵抗未来发展及其并发症（包括肥胖，T2DM和CVD）的儿童风险因素的影响。从该研究建议获得的信息将构成我们未来对童年和成人疾病危险因素的前机会与其他UTERO事件计划的机制进行调查的基础。