Insulin Resistance and Glucose and Lipid Metabolism in Pregnancy

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DESCRIPTION (provided by applicant): The long term objectives of this project are to characterize and understand the mechanisms by which pregravid and early pregnancy maternal metabolism relate to increased fetal growth/adiposity among obese women. Obesity is becoming an epidemic not only in the developed nations of the world but also in developing countries, affecting not only adults and adolescents but possibly even newborns. This proposal has 3 specific aims. Specific aim 1 is to evaluate the affect of maternal obesity on placental growth and gene expression in vivo and in vitro. We hypothesize that obese women because of decreased insulin sensitivity have an increased insulin response which results in increased placental growth possibly through modulation of adipokine and lipid gene expression. Specific aim 2 is to evaluate the longitudinal changes in maternal white adipose tissue (WAT) lipid metabolism from pregravid to early pregnancy in lean women. We hypothesize that in early pregnancy there is decreased lipolysis, increased insulin suppression of lipolysis of WAT resulting in increased accretion of maternal fat mass. Consequently, the increase in WAT results in increased modulation of adipokines resulting in decreased insulin sensitivity. Specific aim 3 is to evaluate the longitudinal changes in maternal WAT lipid metabolism from pregravid to early pregnancy in obese women. We hypothesize that because obese women have decreased insulin sensitivity relative to lean women, they have increased basal lipolysis, decreased suppression of lipolysis both pregravid and in pregnancy resulting in increased lipid availability for transfer to the fetus. Because there is no accretion or loss of maternal WAT, there is no change or decrease in expression of adipokines resulting in either no change or increase in insulin sensitivity relative to pregravid measures. By performing the detailed physiologic studies in vivo combined with the in vitro experiments in a prospective longitudinal study design, we will be able to test our hypotheses in a definitive manner. We will identify mechanisms for the observed physiologic changes and neonatal outcome of fetal obesity, defined as an increase in adipose tissue based on our population normative data. If our hypotheses are correct, these studies will then provide us with a rational basis for interventional studies to possibly prevent fetal obesity which we believe is a significant risk factor the increased prevalence of the metabolic syndrome in the population.