Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes - Biostatistics Research Center

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Project Summary/Abstract Type 2 diabetes (T2D) in youth is increasingly prevalent in parallel with the obesity epidemic, yet effective treatment and prevention strategies are limited. The physiologic reduction in insulin sensitivity occurring during puberty in combination with obesity-related insulin resistance enhance the risk of T2D. Yet it remains unclear why some youth experience normal pubertal progression with intact β-cell function, while others do not, despite similar phenotypic and metabolic characteristics. The low incidence and prevalence of T2D in youth compared to adult’s turns the focus to identifying and characterizing pathophysiological precursors to T2D. More information is needed regarding the unique events during puberty to better understand the basic pathophysiology of glucose control, insulin sensitivity, β-cell function, and T2D risk in youth, as well as differences by sex/gender and race/ethnicity, and the potential contribution of harmful environmental factors that are characteristic of this population. Importantly, this research needs to address the timeline of pathophysiological activity from normoglycemia to prediabetes to youth-onset T2D (YO-T2D). The Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes (UTP-T2D) Consortium provides a unique opportunity to characterize the risk progression profile and mechanisms underlying the development of YO-T2D, and evaluate the effects of modifiable and non-modifiable risk factors. Ultimately, the results of this study will establish a basic pathophysiology to inform future studies aimed at achieving glycemic control, improving insulin sensitivity, preserving β-cell function, and/or preventing T2D in youth. To address this goal, the UTP-T2D study will recruit, enroll, and follow a large racially and ethnically diverse cohort of 3,000 at- risk obese youth in early puberty, extensively phenotype them as they transition through puberty, and characterize the course of decline and dysfunction in pathophysiological indicators that lead to T2D. The expected duration of the UTP-T2D study is 5 years, including planning, recruitment, follow-up, analysis, and reporting. In addition to addressing the aims with analyses conducted as part of the proposed study, the UTP- T2D consortium will store longitudinal biospecimens and genetic material with the intention of acquiring additional ancillary funding to pursue analysis of emerging indicators. The Biostatistics Research Center (BRC) will enhance the value of the UTP-T2D Consortium by 1) overseeing all operational aspects of the Consortium, 2) providing administrative resources and logical support of the Consortium, and 3) providing scientific and biostatistical expertise for the Consortium. Through effective organization, communication, and support, and by promoting a collaborative environment, the BRC will provide the framework and infrastructure for the Consortium to successfully recruit a cohort of early pubertal youth at risk for developing prediabetes and T2D, deeply phenotype them through puberty, and ultimately contribute to a better understanding of the pathophysiology of YO-T2D.