Cincinnati Children's Clinical Center for Targeting the Pathophysiology of Youth-Onset Type 2 Diabetes

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PROJECT SUMMARY For more than two decades through local and multi-center studies our team at Cincinnati Children’s Hospital has documented the epidemiology of youth-onset type 2 diabetes (T2D) in the US and its associated early-onset co- morbidities and complications. Furthermore, recent studies show current therapies do not slow or prevent the progression of youth-onset T2D once it has started, highlighting the aggressive nature of this condition and the critical need for prevention. Unfortunately, studies to date have failed to yield a sufficient number of youths who have developed T2D, limiting the ability to define who is at risk and the underlying pathophysiology. As such, we have developed a prospective, longitudinal observational cohort study along with a series of hypothesis driven investigations to uncover the pathophysiology leading to youth-onset T2D directly addressing the overarching objective of this U01 funding opportunity. We propose to recruit a cohort of youth, selected for risk factors associated with the development of type 2 diabetes. This cohort will undergo detailed studies of pancreatic beta (β) cell function that include measures of insulin sensitivity and secretion. These studies will be coupled with assessment of genetics, adiposity, metabolic factors, behavioral and psychosocial risks to elucidate how these factors influence β-cell function and progression to T2D. Monitoring the proportion of youth in the cohort who develop T2D and the frequency of associated co-morbidities will fulfill Aim 1, while assessing β-cell function during puberty and the genetic, metabolic and hormonal factors associated with β-cell function will complete Aim 2. Aim 3, will be achieved by evaluating the role of behavioral and psychosocial factors on β-cell function and progression to T2D. Cincinnati Children’s Hospital has longstanding, proven clinical and research expertise in pediatric obesity and youth-onset type 2 diabetes and experience performing complex studies of pancreatic β- cell function including frequently sampled intravenous glucose tolerance testing, clamp studies, and oral glucose tolerance testing. Our site also has high patient volumes of race/ethnicity, urban/rural, and socioeconomic diverse clinical cohorts with documented ability to recruit and retain participants in our prior NIH funded studies, and we have successfully collaborated in many pediatric multicenter studies. Thus, we are well positioned to partner in this U01 consortium to advance our understanding of the pathophysiology to youth-onset T2D. This proposal will refine the phenotype of youth at greatest risk for T2D and identify factors that influence β-cell function and the progression to T2D. This will position the consortium to develop targeted interventions to prevent youth-onset T2D as a next step.