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

项目总结/摘要 在子宫内暴露于母体糖尿病，无论是哪种类型，都会增加肥胖、胰岛素 抵抗、糖尿病、肾损害和心血管疾病。然而，水平和 胎儿发育期间高血糖暴露的时间，触发这些远程，跨代 病理结果仍然未知。识别有风险的后代，以及启动的最佳时间 潜在的预防措施对于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改善， 先天性畸形（最常见的是心脏畸形）和围产期死亡率从17% 和16%，现在接近非糖尿病妊娠的发生率。然而，其他后代 结果，包括肥胖，代谢和临床前心血管疾病未能下降。是 关键是快速和直接确定子宫内环境的具体贡献，这些更多 影响1型糖尿病女性成年后代的微妙病理生理学和临床前疾病 孕期这项提案利用了一个独特的数据集和我们重新研究一个既定的 队列，将解决这一关键差距，直接通知临床管理，并提醒孕妇自己， 关于妊娠期高血糖波动对其后代的终生影响。 这一建议的中心假设是，成年人在子宫内暴露于高血糖，将有 肥胖、胰岛素抵抗、糖尿病、肾脏和心血管损害的风险增加。为了验证这一 假设我们将完成以下具体目标。具体目标1：证明 高血糖宫内环境对成年人代谢健康的跨代影响 女性1型糖尿病患者的后代。我们将确定高血糖的敏感妊娠期 预测成年后代的特定代谢发病率。具体目标2：证明 高血糖宫内环境对心脏和外周血管的跨代影响 1型糖尿病女性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鉴定的母体血糖谱来预测， 表征葡萄糖控制水平和变异性。 这项跨代队列研究将采用创新的统计方法， 和1型糖尿病妇女的母亲患病率与成年后代发病率的差异。的 在首次妊娠期间前瞻性收集的数据粒度显著，并结合新数据 从成年后代和我们的新的统计方法，将使我们能够确定的组成部分， 子宫内血糖环境导致成年后代的特定发病率和疾病风险。

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.