PROJECT SUMMARY Obesity and subsequently type 2 diabetes (T2D) is increasingly common in adolescents, but the phenotype of youth-onset T2D (YO-T2D) differs from adults. The NIDDK TODAY study we helped lead, demonstrated that youth with T2D had a high (≈50%) and rapid failure rate on oral medications and faster need for insulin therapy vs. adults treated for a similar duration in the ADOPT study. As further evidence, in our NIDDK RISE study, where treatment responses in youth with impaired glucose tolerance (IGT) or newly diagnosed T2D were directly compared to adults of similar BMI and initial glycemia, youth were twice as insulin resistant as adults and had rapid deterioration of β-cell function and glycemic control compared to adults given the same treatment with similar medication adherence. Finally in our HIP study, metformin did not improve insulin sensitivity or secretion even when started early in puberty in normoglycemic youth with obesity, arguing for innovative approaches. Of most concern, TODAY demonstrated an incidence of microvascular diabetes complications ranging from 32-68% by a mean age of only 26.4±2.8 yrs, affecting individuals who should be at their peak of productivity; complications more heavily affected those with minority race/ethnicity, raising concerns related to health disparities. This unprecedented early morbidity and projected health care costs mandate a focus on defining a) the ideal T2D diagnostic and/or screening criteria for youth b) pathophysiologic distinctions between Y-T2D and adult-onset T2D c) how to prevent Y-T2D d) how to better treat Y-T2D once present. Though some risk factors for developing Y-T2D (e.g. family history, obesity, etc.) are well-established, only a small subset of these high-risk youth progress to T2D as adolescents. Thus, other causal components need to be explored, such as adverse childhood experiences, stress, poverty, racism, sleep/circadian rhythm, subtle differences within sedentary behavior, and the exact impact(s) of pubertal hormones. We propose to enroll and follow longitudinally 3,540 diverse youth (236 from our site) at risk for developing T2D from urban and rural locations who are early in puberty, and perform longitudinal assessments every 6 mo (HbA1c, Taneda scale every 6 mo, OGTT/DXA/MRI, yearly) paired with additional sample storage to be analyzed once a “critical mass” of youth with new-onset T2D is accumulated. We propose the following Specific Aims, developed in collaboration with our stakeholders/community members from populations disproportionately affected by T2D: 1. To assess patterns of change in metabolic and pubertal events, we will measure: glycemia, insulin sensitivity/secretion, body composition, free living behaviors, and pubertal hormones, as well as bank blood, stool, hair, and urine. 2. To assess psychosocial and psychological factors, we will measure stress, discrimination, teasing, microaggressions, social status, access to care, depression/anxiety, and cortisol. 3. To use the data collected in Aims 1 and 2 and apply unbiased data analysis methodology to identify biomarkers for progression risk and develop a prediction model for who will develop Y-T2D.

PROJECT NARRATIVE Obesity and subsequently type 2 diabetes are increasingly common in pubertal youth, and with a greater degree of insulin resistance, earlier onset of beta-cell failure, and earlier need for insulin therapy than in adults. Medication responses in existing studies in youth-onset type 2 diabetes are poorer than similar studies in adults, with evidence that this aggressive phenotype is leading to earlier onset of diabetes complications. As a result, we now propose to recruit youth with obesity early in puberty and follow them longitudinally over time with serial assessments of insulin sensitivity and secretion, free-living glycemia, physical activity and sleep, mental health and stress, body composition, pubertal stage, and store samples for additional future analyses, with a new focus on understanding the unique, early contributors to development of type 2 diabetes in youth.