The long term objective of this application is to examine the importance of progravid maternal insulin sensitivity on the maternal metabolic adaptations during pregnancy.
The specific aims of the proposal are 1) to characterize the longitudinal changes in maternal carbohydrate metabolism in obese control subjects and obese women with gestational diabetes prior to conception and in early and late gestation and 2) to determine if the changes in maternal energy expenditure and body composition in early gestation are related to alterations in maternal carbohydrate metabolism. We plan to achieve the first specific aim by longitudinally evaluating 7 obese women subjects will be evaluated using: 1) the oral glucose tolerance test, 2) intravenous glucose tolerance test, 3) hydrodensitometry, and 4) a low and high dose hyperinsulinemic- euglycemic clamp coupled with glucose infusion. The specific methodology will allow evaluation of: 10 insulin response, 2) basal endogenous glucose production and suppression with a low and high insulin infusion and 3) calculation of an insulin sensitivity slope. We plan to achieve the second specific aim by evaluating the 14 subjects described in the first specific aim and 7 additional lean subjects prior to conception and in early gestation using the same specific methodology in the first specific aim plus: 1) indirect calorimetry, 2) hydrodensitometry corrected for total body water and 3) doubly labelled water. The specific methodology will allow us to evaluate 1) energy expenditure in the basal state and during insulin infusion, 2) the route of glucose disposal, i.e. oxidative vs non-oxidative, 3) maternal body composition and 4) total energy expenditure in the free living state over 12 days. The information obtained from theses studies will provide us with the information to develop clinical methodologies to diagnose and treat gestational diabetes earlier in gestation based on the specific metabolic abnormality.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Case Western Reserve University
Obstetrics & Gynecology
Schools of Medicine
United States
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Berggren, E K; O'Tierney-Ginn, P; Lewis, S et al. (2017) Variations in resting energy expenditure: impact on gestational weight gain. Am J Obstet Gynecol 217:445.e1-445.e6
Catalano, Patrick M; Shankar, Kartik (2017) Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ 356:j1
Ma, Ronald Ching Wan; Schmidt, Maria Ines; Tam, Wing Hung et al. (2016) Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and post partum. Lancet Diabetes Endocrinol 4:1037-1049
Yang, Xiaohua; Li, Ming; Haghiac, Maricela et al. (2016) Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface. Diabetologia 59:2459-2466
Catalano, P; deMouzon, S H (2015) Maternal obesity and metabolic risk to the offspring: why lifestyle interventions may have not achieved the desired outcomes. Int J Obes (Lond) 39:642-9
Lassance, Luciana; Haghiac, Maricela; Leahy, Patrick et al. (2015) Identification of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstet Gynecol 212:647.e1-11
O'Tierney-Ginn, Perrie; Presley, Larraine; Myers, Stephen et al. (2015) Placental growth response to maternal insulin in early pregnancy. J Clin Endocrinol Metab 100:159-65
Yang, Xiaohua; Haghiac, Maricela; Glazebrook, Patricia et al. (2015) Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts. Hum Reprod 30:2152-9
Lassance, Luciana; Haghiac, Maricela; Minium, Judi et al. (2015) Obesity-induced down-regulation of the mitochondrial translocator protein (TSPO) impairs placental steroid production. J Clin Endocrinol Metab 100:E11-8
Berggren, Erica K; Presley, Larraine; Amini, Saeid B et al. (2015) Are the metabolic changes of pregnancy reversible in the first year postpartum? Diabetologia 58:1561-8

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