DESCRIPTION (provided by applicant): Offspring of mothers with obesity and/or pre-existing or gestational diabetes mellitus (GDM) during pregnancy are at increased risk for obesity and altered glucose metabolism as children and adults, leading to a proposed "transgenerational cycle of obesity and diabetes" wherein maternal diabetes and/or obesity in pregnancy beget more diabetes and obesity. The mechanisms underlying these risks are not known, but the mother's metabolic profile impacts the intrauterine milieu of the developing fetus as glucose and other molecules cross the placenta and impact fetal growth and development. We are hypothesizing that analytes comprising distinct metabolic signatures will demonstrate association with newborn anthropometric traits as well as maternal glycemic and anthropometric traits and that offspring of mothers with GDM (defined using the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria) and/or obesity will exhibit a metabolic profile similar to that associated with newborn adiposity, regardless of their adiposity. We will address this hypothesis using metabolomics, a technology capable of defining the metabolic profile present in different physiologic or pathophysiologic conditions, and a unique resource, stored serum samples from ~23,000 mothers and their offspring who were enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The General Aim of the proposed HAPO Metabolomics Study is to use a targeted mass spectrometry- based platform to measure amino acids, acylcarnitines, and conventional metabolites and a gas chromatography:mass spectrometry-based non-targeted platform to analyze a wide variety of metabolites to define the metabolic profile of 1,600 Northern European ancestry, Afro-Caribbean, Mexican-American and Thai mother-offspring pairs at ~28 weeks gestation (in mothers) and birth (in offspring). The following Specific Aims will be addressed. (i) To test the hypothesis that distinct metabolic signatures are independently associated with maternal metabolic traits (fasting, 1 hr., and 2 hr. glucose and insulin sensitivity) determined by an oral glucose tolerance test (OGTT) and body mass index (BMI) at the time of the OGTT. (ii) To test the hypothesis that the above metabolic profiles will be evident during pregnancy in mothers of newborns at increased risk for metabolic diseases by determining metabolic profiles for mothers that independently associate with GDM and obesity during pregnancy. (iii) To test the hypothesis that a distinct metabolic signature in mothers and newborns is associated with newborn anthropometric traits at birth including birth weight, sum of skinfolds, and percent body fat. (iv) To test the hypothesis that newborns at risk for metabolic diseases in childhood and/or adulthood secondary to maternal GDM and/or obesity have distinct metabolic profiles at birth by determining metabolic profiles in newborns that independently associate with GDM and maternal obesity during pregnancy. Together, these studies will have an important impact on our understanding of the metabolic underpinnings of the increased risk of metabolic diseases in newborns of mothers with hyperglycemia and/or obesity.

Newborn fatness and birth weight can have long term health consequences through an impact on later risk of obesity and altered glucose metabolism as children and adults. Offspring of mothers who are obese or have gestational diabetes during pregnancy have a clear increase in risk, and it has been suggested that they are then more likely to expose their offspring to obesity and gestational diabetes during pregnancy, thus establishing a "transgenerational cycle" of obesity and diabetes. It is not known how the intrauterine environment, especially in the setting of obesity and/or gestational diabetes, confers these risks, and the goal of this proposal is to characterize how the intrauterine environment may impact newborn fatness and birth weight, including in the setting of maternal obesity or gestational diabetes, to begin to define the underlying genesis of the long term risks to the offspring.