Youth-Onset Type 2 Diabetes and Heart Disease: The Young at Heart Prospective Cohort Study

Study Description: This study will evaluate the pathophysiological features of cardiovascular disease in youth-onset type 2 diabetes (Y-T2DM) using a multi-level, multi-domain approach of socio-ecological risk factors (societal, community, and individual). We will employ a prospective, observational study design in youth aged 12-25 years to compare Y-T2DM with age and BMI-matched youth with overweight or obesity (Y-OW) and age-matched healthy lean peers (Y-Lean). The study will also include a single-day visit for biological parents of enrolled Y-T2DM, Y-OW and Y- lean, to assess parental factors involved in the pathophysiology of cardiovascular disease in Y-T2DM. Objectives: Primary Objectives: * To compare pulse wave velocity (PWV) at baseline in Y-T2DM vs Y-OW and age-matched peers Y-Lean. * To compare augmentation index (Aix) at baseline in Y-T2DM vs Y-OW and age-matched peers Y-Lean. * To compare pulse wave velocity (PWV) at 5 years in Y-T2DM vs Y-OW and age-matched peers Y-Lean. * To compare augmentation index (Aix) at 5 years in Y-T2DM vs Y-OW and age-matched peers Y-Lean. Secondary Objectives: In Y-T2DM vs. Y-OW vs. Y-Lean youth, * To evaluate coronary artery structure and endothelial function at baseline and 5 years. * To evaluate the relationship of pulse wave velocity and coronary artery structure \& endothelial function with atherogenic and remnant lipoproteins. Exploratory Objectives: In Y-T2DM vs. Y-OW vs. Y-Lean youth, * To evaluate annual change in vascular aging (measured by the change in pulse wave velocity and endothelial function). * To evaluate the relationship of physiologic, psychological stress (measured with the allostatic load score, ALS), psychosocial and behavioral factors with vascular aging. * To evaluate biomarkers for vascular aging; ex. Beta-cell function, insulin resistance, inflammatory markers, and novel lipid parameters. * To evaluate the association of polygenic risk scores (PRS) in Y-T2DM and with changes in glucose and metabolic profiles (e.g., triglycerides) over time. * To evaluate differences in epigenetic aging in youth and parents. * To determine the prevalence rates of major adverse cardiovascular events (MACE) Endpoints: Primary Endpoint: * Carotid-femoral pulse wave velocity (PWV) at baseline * Pulse augmentation index (Aix) at baseline * Carotid-femoral PWV at 5 years * Pulse Aix at 5 years Secondary Endpoints: * Right coronary wall thickness measured by cardiac MRI * Endothelial function measured by MRI isometric handgrip exercise * Fasting and postprandial lipoprotein profile (mixed meal test) Exploratory Endpoints: Markers of vascular aging (annual change): * PWV * Aix * Endothelial function measured by reactive hyperemia index * Right coronary wall thickness measured by MRI * Heart rate variability * Central Retinal Artery Equivalent Markers of physiological stress * Allostatic load score * Cortisol (serum) * C-reactive protein and immune biomarkers Assessment of metabolic variables * Sigma and insulin sensitivity index (standard 75g OGTT) * Postprandial lipoproteins (mixed meal test) * Metabolomics, Lipidomics, Proteomics Measures * Liver fat and function * Body composition Psychosocial, Neighborhood, and individual variables * Psychosocial Assessments: Binge Eating Disorder Screener-7 (BED-7), Brief Resilience Scale, Diabetes Distress Scale (DDS-17), Emotional Eating Scale, Michigan Neuropathy Screening Instrument (MNSI), PROMIS Emotional Distress - Anxiety, PROMIS Emotional Distress - Depression, PROMIS - Sleep Disturbance, Reward-Based Eating Drive Scale (REDS), Self-assessment of Worries, Concerns, and Burdens Related to Diabetes and Preparation for Transitioning, Substance Use, and Stroop Color and Word Test * Neighborhood Assessments: Adverse Childhood Experience (ACE), Confusion, Hubbub, and Order Scale (CHAOS), MacArthur Scale of Subjective Social Status, Neighborhood Disadvantage Scale, Pediatric ACES and Related Life Events Screening (PEARLS), Unpredictability Beliefs Scale, and U.S. Household Food Insecurity Module. * Individual Assessments: dietary, activity, sleep assessment questionnaire, stress-related eating, 7-10-day accelerometer (activity, sleep), 7-10-day continuous glucose monitor Genetic/ Epigenetic * Genome-wide genotyping array * Genome-wide DNA methylation array Five-point MACE * Acute myocardial infarction * Stroke * Cardiovascular mortality * Hospitalization for unstable angina or revascularization procedures * Heart failure