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

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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.