Project Summary Youth-onset type 2 diabetes (T2D) is a heterogeneous disease, more rapidly progressive than adult-onset disease, and is associated with increased comorbidities. Yet, it is not clear which high-risk youth will eventually progress to T2D. T2D pathogenesis is related to complex hormonal mechanisms that result in β-cell dysfunction, influenced by genetic, epigenetic, social and environmental factors. The overarching goal of this proposal is to prevent youth-onset T2D. Our aims are to identify the risk factors and pathophysiologic changes that lead to the development of youth-onset T2D. We will collaborate as a member of a consortium of clinical centers to achieve these aims. We will leverage our community and stakeholders’ engagement, our robust research infrastructure and the diverse high-risk patient population at our Center, to recruit a high-risk diverse cohort of children from early through mid-puberty (age range 8 to 14 years, Tanner stage II-IV at enrollment), with normal glucose tolerance and with prediabetes. We will screen 300 children aiming to retain 200 children longitudinally, perform in-depth assessments and survey them for the progression to T2D. We will investigate complementary pathways which, by disrupting the delicate balance between insulin sensitivity and secretion, are most likely to modulate the risk of progression to T2D in youth. To that end, we will 1) characterize the evolution of β-cell dysfunction in relation to changes in adiposity, sex steroids and growth factors during the pubertal transition. We will combine clinical phenotypes with physiologic measures of glucose tolerance, β-cell function and insulin sensitivity (derived from serial oral glucose tolerance tests), circulating metabolites, body composition and abdominal fat changes (dual-energy X-ray absorptiometry and magnetic resonance imaging); 2) employ novel epigenetic markers of DNA methylation at correlated regions of systemic interindividual variation (CoRSIVs) to evaluate epigenetic changes that may predispose to β-cell dysfunction; and 3) evaluate social and behavioral determinants of health that could lead to long-term disease phenotype through promotion of adiposity and activation of the hypothalamic-pituitary-adrenal axis (as measured by urinary catecholamines and cortisol), and inflammation pathways. Our innovative study design will allow us to determine the evolution of the risk factors for youth-onset T2D during the pubertal transition, the underlying metabolic changes, and the modifying social and environmental effects, in the context of genetic/epigenetic susceptibility. The findings from this study are highly significant to improve the identification of high-risk children vulnerable to progression to T2D, and characterize the pathophysiology of the disease during a critical window of childhood growth and development. The knowledge gained will allow the consortium to develop risk stratification algorithms and design personalized prec...