Metabolic Health during Puberty: the Healthy Start Study

项目总结/摘要 2型糖尿病（T2 D）在全球范围内不断增加，包括成人和青年。青年型T2 D强烈 与肥胖相关，其特征是快速β细胞衰竭，早期发病率和死亡率， 普遍出现在青春期中期，这是一个生理性胰岛素抵抗的时期。 然而，我们对青年发病的T2 D的病理生理学的了解是有限的，因为它主要来自于 横断面研究和纵向研究没有跨越整个青春期过渡期或只包括青年 肥胖症这些研究不能提供对葡萄糖-胰岛素生理变化的理解 青春期的体内平衡，以及先前的代谢健康如何影响它们。我们也知道一些风险 年轻发病的T2 D的因素，但我们不知道他们如何运作。这些差距使我们无法准确地 预测和预防青年发病的T2 D。 这项提案的首要目标是提高我们对代谢健康和失调的理解 以及它们的决定因素。为了实现这一目标，我们建议扩大纵向后续行动， 健康开始（HS）队列，一项基于母婴社区的队列研究，招募了1418名孕妇， 妇女，并对怀孕期间的母亲、7岁以下的后代进行了详细描述 （R 01 DK 076648），并在8-10岁时持续进行（通过环境对儿童健康的影响 结局-ECHO- Consortium，UH 3 OD 023248）。这个群体现在正经历青春期的转变。 我们将对500名10-15岁的青少年在整个青春期进行随访，以解决特定目标：目标1：描述 血糖轨迹[A1 c，空腹和负荷后血糖，血糖曲线下面积， 口服葡萄糖耐量试验（OGTT）及其代谢相关因素;目的2：探索青春期口服葡萄糖耐量试验的顺序 将早期生活暴露与青春期葡萄糖-胰岛素稳态联系起来的代谢变化;目的3：评估 确定遗传危险因素和表征基因-环境相互作用对青春期发育的重要性 葡萄糖-胰岛素稳态 对青年转变时葡萄糖-胰岛素稳态生理变化的更好理解 将提供基础知识，以更好地预测未来青年发病的T2 D风险。一种改进 了解生命早期暴露导致的代谢变化顺序并影响肥胖 在T2 D遗传易感性的背景下，葡萄糖-胰岛素代谢将为潜在的预防提供信息。 接近。

PROJECT SUMMARY/ABSTRACT Type 2 Diabetes (T2D) has been increasing worldwide, in both adults and youth. Youth-onset T2D is strongly associated with obesity, characterized by rapid β-cell failure, early morbidity and mortality, and it almost universally presents in mid-puberty, a period of physiologic insulin resistance. However, our knowledge of the pathophysiology of youth-onset T2D is limited as it is primarily derived from cross-sectional studies, and longitudinal studies do not span the entire pubertal transition or only include youth with obesity. Such studies are not able to provide an understanding of the physiologic changes in glucose-insulin homeostasis during puberty, and of how prior metabolic health influences them. We also know of several risk factors for youth-onset T2D, but we do not know how they operate. These gaps prevent us from accurately predicting and preventing youth-onset T2D. The overarching goal of this proposal is to improve our understanding of metabolic health and dysregulation during puberty, and their determinants. To address this goal we propose to extend the longitudinal follow-up of the Healthy Start (HS) Cohort, a maternal-offspring community-based cohort study that enrolled 1418 pregnant women and conducted detailed characterization of mothers during pregnancy, of offspring through age ~7 years (R01DK076648), and ongoing at ages 8-10 years (through the Environmental Influences on Child Health Outcomes –ECHO- Consortium, UH3OD023248). This cohort is now transitioning through puberty. We will follow up 500 youth age 10-15 years throughout puberty to address specific aims: Aim 1: Describe glycemic trajectories [A1c, fasting and postload glucose, area under the glucose curve, time to peak during an oral glucose tolerance test-OGTT], and their metabolic correlates, during puberty; Aim 2: Explore the sequence of metabolic changes linking early life exposures to pubertal glucose-insulin homeostasis; Aim 3: Assess the importance of established genetic risk factors and characterize gene-environment interactions on pubertal glucose-insulin homeostasis. An improved understanding of the physiological changes in glucose-insulin homeostasis as youth transition through puberty will provide foundational knowledge to better predict future youth-onset T2D risk. An improved knowledge of the sequence of metabolic changes resulting from early life exposures and influencing adiposity and glucose-insulin metabolism, in the context of genetic susceptibility to T2D, will inform potential prevention approaches.