Level and timing of diabetic hyperglycemia in utero: the transgenerational effect on adult morbidity (TEAM Study)

项目摘要/摘要 在子宫内暴露于母亲糖尿病，无论是哪种类型，都会增加肥胖的风险，胰岛素 子代的抵抗力、糖尿病、肾脏损害和心血管疾病。然而，水平和 在胎儿发育期间暴露高血糖的时机，触发这些遥远的、跨代的 病态的结果，仍然是未知的。识别处于危险中的后代，以及启动的最佳时间 每项可能的预防措施都对改善这些脆弱胎儿的健康结果至关重要。 在过去的半个世纪里，妊娠期1型糖尿病的控制呈指数级增长，导致 先天畸形(最常见的是心脏)和围产儿死亡率从17%下降 和16%，现在接近非糖尿病妊娠的发病率。然而，其他后代 结果，包括肥胖、代谢和临床前心血管疾病都未能下降。它是 对于快速和直接确定宫内环境对这些更多的 影响女性1型糖尿病成年后代的细微病理生理和临床前疾病 在怀孕期间。这一建议，利用了独特的数据集和我们重新研究已建立的 队列，将解决这一关键差距，直接告知临床管理，并提醒孕妇自己， 关于怀孕期间高血糖短途旅行给她的后代带来的终身后果。 这一建议的中心假设是，在子宫内暴露于高血糖的成年人，将会有 肥胖、胰岛素抵抗、糖尿病以及肾脏和心血管损害的风险增加。为了测试这一点 假设我们将完成以下具体目标。具体目标1：展示 宫内高血糖环境对成人代谢健康的代际影响 患有1型糖尿病的妇女的后代。我们将确定高血糖的敏感妊娠期 成年后代特定代谢性疾病的预测。具体目标2：展示 宫内高血糖环境对心脏和外周的代际影响 1型糖尿病患者成年后代的血管结构和功能。我们将确定是否 成年后代的心血管损害可以通过识别的母体血糖曲线来预测， 表现出血糖控制水平和可变性的特点。 这项跨代队列研究将应用创新的统计方法来联系时间、水平 以及母体血糖与1型糖尿病患者成年后代发病率的变异性。这个 与新数据相结合，在指数怀孕期间收集的预期数据的显著粒度 来自成年后代和我们新颖的统计方法，将使我们能够识别 导致成年后代特定发病率和疾病风险的宫内血糖环境。

Project Summary / Abstract Exposure to maternal diabetes mellitus, regardless of type, in utero increases the risk of obesity, insulin resistance, diabetes, renal compromise and cardiovascular disease in offspring. However, the level and timing of hyperglycemic exposure during fetal development, triggering these remote, transgenerational morbid outcomes, remain unknown. The identification of offspring at risk, and of the optimal times to initiate potential preventive measures are each critical for improving the health outcomes of these vulnerable fetuses. Over the past half century, type 1 diabetes control during pregnancy has improved exponentially, resulting in decreased incidence of congenital malformations (most commonly cardiac) and of perinatal mortality from 17% and16%, respectively, to rates which now approach those in non-diabetic pregnancy. However, other offspring outcomes, including obesity, metabolic, and preclinical cardiovascular disease have failed to decline. It is critical to rapidly and directly determine specific contributions of the intrauterine environment to these more subtle pathophysiologies and preclinical diseases affecting adult offspring of women with type 1 diabetes during pregnancy. This proposal, capitalizing on a unique dataset and our ability to re-study an established cohort, will address this key gap, directly inform clinical management, and alert the pregnant woman herself, regarding the lifetime consequences for her offspring due to hyperglycemic excursions during gestation. The central hypothesis for this proposal is that adults exposed in utero to hyperglycemia, will have increased risk of obesity, insulin resistance, diabetes, and renal and cardiovascular compromise. To test this hypothesis we will complete the following specific aims. Specific Aim 1: To demonstrate the transgenerational effect of the hyperglycemic intrauterine environment on metabolic health of adult offspring of women with type 1 diabetes. We will identify sensitive gestational periods of hyperglycemia predictive of specific metabolic morbidities in the adult offspring. Specific Aim 2: To demonstrate the transgenerational effect of the hyperglycemic intrauterine environment on cardiac and peripheral vascular structure and function in adult offspring of women with type 1 diabetes. We will determine if cardiovascular compromise in the adult offspring may be predicted by an identified maternal glycemic profile, characterizing both level of glucose control and variability. This transgenerational cohort study will apply innovative statistical approaches to relate timing, level and variability of maternal glycemia to morbidity in adult offspring of women with type 1 diabetes. The remarkable granularity of data collected prospectively during the index pregnancies, combined with new data from the adult offspring and our novel statistical methods, will enable us to identify components of the intrauterine glycemic environment that contribute to specific morbidities and disease risk in the adult offspring.