Illuminating the path(ophysiology) to development of youth-onset type 2 diabetes (PATH-NC)

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ABSTRACT Estimates suggest that across a period of just 16 years (2001-2017), prevalence of T2D in youth has doubled, from an estimated prevalence of 0.34 per 1000 youths to 0.67 per 1000 youths. Through our work on the SEARCH for Diabetes in Youth Study (SEARCH) we have reported that the incidence of T2D is disproportionately experienced in marginalized racial and ethnic minority groups, with American Indian and non-Hispanic Black youth experiencing the greatest burden of T2D. We have demonstrated that the well- known complications and comorbidities of adult-onset T2D, including diabetic nephropathy, retinopathy, peripheral neuropathy, arterial stiffness, and hypertension, have an accelerated onset in youth onset T2D. While it has been well-established that overweight and obesity, together with family history, are associated with increased risk for development of youth onset T2D, the majority of youth with these risk factors do not develop T2D. T2D rarely occurs prior to the onset of puberty and it is well-established that puberty is associated with a decrease in insulin sensitivity, with nadir experienced typically at Tanner Stage III, before returning to pre- pubertal levels by Tanner Stage V in the healthy adolescent. Youth appear to be at greatest risk for development of T2D as they progress toward the latter stages of puberty. We propose a longitudinal cohort study designed to provide deep phenotyping of pathophysiologic markers across the pubertal transition for high-risk youth with obesity, assessing these factors in relation to underexplored social, behavioral, and early life risk factors for development of T2D in youth. As one of many clinical sites supporting this Consortium, we are prepared to enroll 504 youth, from a highly diverse population of youth with obesity and in early to mid- puberty (Tanner Stage II or III). Operational aims include recruiting and retaining a diverse cohort of at-risk youth (OA1), sustaining stakeholder engagement to inform the study throughout study planning, implementation, and dissemination (OA2), and establishing a biobank of participant specimens and samples from which future ancillary studies can be conducted (OA3). The Scientific Aims supported by these Operational Aims address the overarching objectives of conducting deep phenotypic characterization of youth- onset T2D, including assessment of physiologic markers across the pubertal transition (SA 1.), establishing social and behavioral risk factors for and protective factors against development of youth onset T2D, beyond that which has already been established (SA 2.), and evaluating genetic and epigenetic data to further mechanistic understanding of disease pathogenesis in youth (SA 3.). Ultimately, this work will support increased understanding of which individuals are at risk for developing youth-onset T2D and allow identification of determinants of progression from prediabetes to T2D, which will support groundbreaking future prevention approaches that, once evaluated, could be tailored to individual risk.