Metabolic Health during Puberty: the Healthy Start Study

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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.