Type 2 diabetes (T2D), a condition marked by substantial physical and psychological morbidity, is increasingly diagnosed in youth but is still infrequent even in high-risk obese adolescents. There are significant racial, ethnic, and socioeconomic effects in youth at risk for the development of T2D, but we do not know how to easily identify which youth will and will not develop T2D, nor do we know specifics about the mechanisms behind the early development of T2D. To address these research gaps amongst others, we propose an appropriately powered prospective cohort study of 3500 youth in response to RFA DK-21-002 Understanding and Targeting the Pathophysiology of Youth-Onset Type 2 Diabetes-Clinical Centers. As the Columbus Clinical Center (CCC), our interdisciplinary team will leverage our large clinical network in urban and rural settings in Ohio AND cumulative experience and expertise caring for youth with obesity and type 2 diabetes, recruiting and retention in prospective clinical/cohort trials and diagnostic testing for diabetes. In addition, we propose mechanistic studies drawing from our prior studies on insulin sensitivity and secretion, β-cell function, innate immune response genes, inflammatory markers, and microbiome. As the CCC, we plan to recruit and retain a cohort of 250 youth aged 9-13 years with obesity (age and sex-specific body mass index (BMI) ≥ 95%tile) with impaired fasting glucose (IFG) (100-125mg/dl) or impaired glucose tolerance (IGT) (140–199mg/dl) in urban and rural Ohio counties over 30 months and propose. Subjects will be followed to determine the pattern and trajectory of anthropometric change (weight, BMI, Tanner stage) as risk factors for T2D, and to investigate a risk phenotype for youth for T2D based on a) social determinants of health, b) lifestyle behaviors and c) psychosocial factors. Oral glucose tolerance tests will be performed every 6 months to diagnosis diabetes and also to assess insulin sensitivity and secretion changes that identify early risk for development of T2D. Continuous glucose monitoring (CGM) and hemoglobin A1c levels will also be assessed throughout the study to identify early markers for development of T2D. Lastly, blood and stool samples will be collected and saved for future assessment of genetic, inflammatory and microbiome factors that play a mechanistic role in the development of T2D. The results of this study will have broad clinical and social impact by identifying youth specifically at risk for T2D and by identifying specific psychosocial risk factors for adolescent T2D. They will have research impact by identifying mechanistic factors for the development of adolescent T2D that may be targeted in future interventional studies to prevent the disease.

As obesity increases in adolescents type 2 diabetes is also increasing. We do not know why T2D happens in some adolescents but not others or how to identify which adolescents will develop diabetes. This multicenter clinical study is designed to follow a large group of youth at-risk for T2D over 30 months and to identify differences in a variety of factors between those who do and do not develop diabetes.