Project Summary/Abstract Increases in pediatric obesity have led to an increased burden of youth-onset (Yo) type 2 diabetes (T2D), disproportionately affecting vulnerable youth. YoT2D is characterized by extreme insulin resistance, insulin hypersecretion, rapid b cell failure, and increased complications compared to adult T2D, raising concern for significant morbidity very early in life. However, the mechanism(s) and risk factors that cause some adolescents with prediabetes (PreDM) to progress to YoT2D while others do not, remain poorly understood. This proposal will study early pubertal youth at risk for YoT2D, to develop more precise prediction paradigms of progression to YoT2D, and to investigate pathophysiologic drivers. YoT2D disproportionately affects racial and ethnic minorities, often with multiple socioeconomic stressors, and the impact of social determinants of health (SDoH) on progression to YoT2D must be clarified. Dr. Sheela N. Magge (PI) has assembled a highly- experienced team from Johns Hopkins sites in Baltimore and Florida, including primary care pediatricians (Perrin, Polk, Showell, Hernandez) at clinics serving large Black and Hispanic populations with socioeconomic disadvantage. Participation in research by minoritized groups is influenced by the trustworthiness of the health system, and study recruitment will be aided by leveraging these trusted care providers. Dr. Magge proposes an innovative approach, recruiting from 3 distinct sources: 1. pediatric subspecialty clinics (endocrinology and obesity), 2. general pediatric clinics serving low-income children of color, and 3. offspring of adults with early onset (£40yrs) T2D. The study will longitudinally follow this cohort (total N=2250) of 9-13 year old girls and 10- 14 year old boys (site n=150) with BMI ≥ 85%ile and PreDM, as defined by HbA1c, fasting glucose, and/or 2-hr glucose on oral glucose tolerance test (OGTT), over 3 years or diagnosis of T2D, whichever occurs first. They will collect anthropometric, cardiovascular, behavioral, and genetic risk factors, as well as SDoH measures. Physiologic testing, including mathematical modelling of insulin kinetics and free fatty acid flux (FFA) using a 3- hour OGTT, in vivo continuous glucose monitoring (CGM), and body composition, will be collected. Aims: 1) To develop reliable estimates of YoT2D risk in youth with PreDM, overall and according to risk factor profiles that differentiate groups based on their risk of progression to YoT2D, 2) To characterize the early pathophysiologic drivers of YoT2D. a. To study differences in insulin kinetics (secretion, sensitivity, clearance), FFA flux, CGM, ectopic fat (visceral, hepatic), and cardiovascular risk between youth who progress to YoT2D and those who do not. b. To determine whether these pathophysiologic differences differ by risk factor groups identified in Aim 1. This proposal employs a multidisciplinary team with a novel mix of expertise in SDoH, stakeholder engagement, and me...