围产期代谢因子和氧化应激与胎儿过度生长相关的糖代谢"编程"

Numerous studies have demonstrated that the susceptibility to type 2 diabetes and other "metabolic syndrome" related disorders may originate from fetal life (fetal "programming"). There is a U-shaped relationship between the incidence of type 2 diabetes and birth weight, subjects with either poor or excessive fetal growth are at significantly increased risk. Excessive fetal growth has become an increasingly more important problem due to the epidemic of modern lifestyle-related issues (obesity，etc.). However, little is known about the mechanisms and perinatal biomarkers of glucose metabolic programming associated with excessive fetal growth. There is a particular lack of mechanistic biomarker data on metabolic programming in humans. Fetal overgrowth has been associated with elevated metabolic hormone and oxidative stress levels. Therefore, we hypothesize that perinatal high metabolic hormone levels and oxidative stress may be the triggers in glucose metabolic programming associated with fetal overgrowth. We propose a prospective pregnancy cohort study to collect clinical data and biological specimens in pregnant women and their infants to test this hypothesis. We will examine whether metabolic factors and oxidative stress are associated with indicators of glucose metabolic function in the offspring, and explore the potential roles of epigenetic changes in certain insulin sensitivity-related genes. The principal applicant has successful experience in North America as the principal investigator in prospective pregnancy cohort studies on fetal growth and glucose metabolism. The present study will likely contribute new knowledge on the mechanisms and relevant perinatal biomarkers of glucose metabolic programming in early life at the international forefront, and contribute new knowledge to early prevention of diabetes.

大量研究证明II型糖尿病等"代谢综合征"相关疾病的易感性可源于胎儿期（胎源"编程"），其发病率与出生体重呈U型关系，宫内生长不良或过度者发病风险都显著升高。由于现代生活方式相关问题流行（肥胖等）, 胎儿过度生长已成日益重要问题。但对胎儿过度生长相关的糖代谢编程的发生机制和相关生物标记所知甚少, 特别缺乏人群研究。胎儿过度生长与代谢因子/激素水平升高和氧化应激相关。因此推测高代谢因子水平和氧化应激可能是胎儿过度生长相关糖代谢编程的触发机制。我们将开展一前瞻性妊娠队列研究收集孕妇和婴儿的临床数据和生物样本检验这个假设，评估围产期代谢因子和氧化应激水平是否与婴儿糖代谢功能相关，探索胰岛素敏感性相关基因表观遗传修饰的可能作用。申请人有在北美主持开展妊娠队列研究胎儿生长和糖代谢的成功经验。本研究将可能对生命早期糖代谢编程的机制和相关生物标记作出国际前沿性的新贡献，为糖尿病的早期预防提供依据。

胎儿过度生长可“编程”对代谢综合征及2型糖尿病的易感性，但其机制仍然不清楚。 我们建立了前瞻性妊娠/出生队列，收集孕妇孕期和婴儿的临床数据和生物样本（母血，胎儿脐带血及胎盘），研究分析了氧化应激，代谢因子，抗氧化剂维生素A及E和营养素长链不饱和脂肪酸及对婴儿胰岛素敏感性和胰岛beta细胞功能等代谢健康指标的影响及在胎儿过度生长中的变化，探索相关的特异性基因甲基化改变。首次发现：1）围产期氧化应激可能在生命早期抑制胎儿的Ghrelin的分泌，提示氧化应激对Ghrelin的影响可能是“编程”影响子代远期代谢疾病风险的机制； 2）低密度脂蛋白氧化产物OxLDL在生命早期可能会损害胰岛细胞的功能； 3）孕妇吸烟（导致氧化应激的常见因素）可影响婴儿胰岛beta细胞的功能；4）生命早期抗氧化剂维生素A 及E的营养素水平可能会影响胎儿的代谢健康；维生素A/视黄醇对胎儿的IGF-1水平有性别特异性的影响（仅影响女孩）; 5）妊娠糖尿病（导致胎儿过度生长的常见因素）可影响孕晚期母血循环中重要营养素脂肪酸DHA和n-3长链不饱和脂肪酸的水平的正常上升；而这种变化可能是由于体内DHA和n-3长链不饱和脂肪酸合成或动员的受损，而不是膳食摄入量的差异。研究结果揭示了氧化应激及代谢因子相关因素在糖代谢编程中的作用，阐明了重要营养素脂肪酸DHA和n-3长链不饱和脂肪酸水平在妊娠糖尿病中的异常变化。研究的发现为预防生命早期不良编程对子代的糖代谢健康的不良影响提供了新线索。