Maternal Obesity and Gestational Diabetes: Impact on Metabolome

描述(申请人提供)：患有肥胖和/或先前存在或妊娠期糖尿病(GDM)的母亲的后代在儿童和成年时患肥胖症和葡萄糖代谢改变的风险增加，导致拟议的“肥胖和糖尿病的跨代循环”，其中母亲怀孕期间的糖尿病和/或肥胖会导致更多的糖尿病和肥胖症。这些风险的潜在机制尚不清楚，但母亲的代谢状况会影响发育中胎儿的宫内环境，因为葡萄糖和其他分子会穿过胎盘，影响胎儿的生长和发育。我们假设，包含不同代谢特征的分析物将证明与新生儿人体测量特征以及母亲的血糖和人体测量特征有关，患有妊娠期糖尿病(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类似的代谢特征，无论他们的肥胖程度如何。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在不同生理或病理生理条件下存在的代谢谱的技术，以及一个独特的资源，存储了来自参与高血糖和不良妊娠结局(HAPO)研究的约23,000名母亲及其子女的血清样本。拟议的HAPO代谢组学研究的总体目标是使用一个基于靶向质谱学的平台来测量氨基酸、酰肉碱和常规代谢物，以及一个基于气相色谱：基于非靶向质谱学的平台来分析各种代谢物，以确定1,600对北欧血统、非洲-加勒比血统、墨西哥-美国和泰国母子代在怀孕~28周(母亲)和分娩(子代)时的代谢谱。将实现以下具体目标。(I)检验不同的代谢特征与母体代谢特征(禁食、1小时和2小时)独立相关的假设。血糖和胰岛素敏感性)由口服葡萄糖耐量试验(OGTT)和体重指数(BMI)测定。(Ii)通过确定孕期与妊娠期糖尿病和肥胖症独立相关的母亲的代谢情况，来检验上述代谢情况在母亲怀孕期间将明显存在的假设，这些母亲患代谢性疾病的风险较高。(Iii)检验一种假设，即母亲和新生儿的明显代谢特征与新生儿出生时的人体测量特征有关，包括出生体重、皮褶总和和体脂百分比。(Iv)通过确定与妊娠期糖尿病和孕妇肥胖症独立相关的新生儿的代谢谱，检验以下假设，即母亲妊娠期糖尿病和/或肥胖继发的儿童和/或成年期代谢性疾病风险的新生儿在出生时具有不同的代谢谱。总之，这些研究将对我们理解母亲患有高血糖和/或肥胖的新生儿患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.