Maternal Obesity and Gestational Diabetes: Impact on Metabolome

描述（由申请人提供）：怀孕期间患有肥胖和/或既往或妊娠期糖尿病（GDM）的母亲的后代在儿童和成人时期肥胖和糖代谢改变的风险增加，导致提出的“肥胖和糖尿病的跨代循环”，其中母亲的糖尿病和/或妊娠期肥胖会导致更多的糖尿病和肥胖。这些风险的机制尚不清楚，但母亲的代谢状况会影响胎儿发育中的宫内环境，因为葡萄糖和其他分子会穿过胎盘，影响胎儿的生长发育。我们假设，包含不同代谢特征的分析物将显示与新生儿人体测量特征以及母亲血糖和人体测量特征的关联，并且患有GDM（使用新的国际糖尿病和妊娠研究小组协会（IADPSG）标准定义）和/或肥胖的母亲的后代将表现出与新生儿肥胖相关的代谢谱，无论其肥胖与否。我们将使用代谢组学来解决这一假设，代谢组学是一种能够定义不同生理或病理生理条件下存在的代谢谱的技术，以及一种独特的资源，即来自约23,000名参加高血糖和不良妊娠结局（HAPO）研究的母亲及其后代的血清样本。拟议的HAPO代谢组学研究的总体目标是使用基于靶向质谱的平台来测量氨基酸，酰基肉碱和传统代谢物，并使用基于气相色谱：质谱的非靶向平台来分析各种代谢物，以确定1600名北欧血统，非洲-加勒比人，墨西哥裔美国人和泰国人的母亲-后代对在妊娠~28周（母亲）和出生（后代）时的代谢谱。以下具体目标将被处理。(i)为了检验不同的代谢特征与母体代谢特征独立相关的假设(禁食，1小时；2小时。葡萄糖和胰岛素敏感性)通过口服葡萄糖耐量试验（OGTT）和OGTT时的体重指数（BMI）来确定。（二）通过确定与妊娠期糖尿病和肥胖有独立关联的母亲的代谢特征，检验上述代谢特征在新生儿患代谢性疾病风险增加的母亲怀孕期间明显存在的假设。（iii）检验母亲和新生儿的独特代谢特征与新生儿出生时的人体测量特征（包括出生体重、皮肤褶皱总数和体脂百分比）相关的假设。（iv）通过确定与妊娠期妊娠糖尿病和妊娠期产妇肥胖独立相关的新生儿代谢谱，检验在儿童期和/或成年期有继发于母体糖尿病和/或肥胖的代谢性疾病风险的新生儿在出生时具有不同的代谢谱的假设。总之，这些研究将对我们理解高血糖和/或肥胖母亲的新生儿代谢性疾病风险增加的代谢基础产生重要影响。

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.