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

摘要 据估计，在短短 16 年期间（2001 年至 2017 年），青少年 T2D 患病率翻了一番， 估计患病率从每 1000 名青年 0.34 人增至每 1000 名青年 0.67 人。通过我们的工作 青少年糖尿病搜索研究 (SEARCH) 我们报告说，T2D 的发病率是 在边缘化种族和少数民族群体中经历过不成比例的经历，其中包括美洲印第安人和 非西班牙裔黑人青年正经历着 T2D 的最大负担。我们已经证明，良好的 成人发病的 T2D 的已知并发症和合并症，包括糖尿病肾病、视网膜病变、 周围神经病变、动脉硬化和高血压在青少年发病的 T2D 中发病加速。 虽然已明确超重和肥胖以及家族史与肥胖有关 青少年患 T2D 的风险增加，大多数具有这些危险因素的青少年不会患上 T2D T2D。 T2D 很少发生在青春期开始之前，并且众所周知，青春期与 胰岛素敏感性下降，通常在 Tanner III 期经历最低点，然后恢复到之前的水平 健康青少年坦纳第五阶段的青春期水平。青少年似乎面临最大的风险 当他们进入青春期后期时，就会出现 T2D。我们提出一个纵向队列 研究旨在提供青春期过渡期间病理生理标志物的深层表型 肥胖的高风险青少年，评估这些与未充分探索的社会、行为和早期相关的因素 青少年患 T2D 的生活风险因素。作为支持该联盟的众多临床中心之一，我们 准备招收 504 名青少年，他们来自高度多样化的肥胖青少年群体以及早期到中期的青少年。 青春期（坦纳第二阶段或第三阶段）。运营目标包括招募和留住多样化的高危群体 青年（OA1），保持利益相关者的参与，以便在整个研究计划过程中为研究提供信息， 实施和传播（OA2），并建立参与者标本和样本的生物库 可以从中进行未来的辅助研究（OA3）。这些所支持的科学目标 运营目标解决了对青年进行深入表型表征的总体目标 发作 T2D，包括评估整个青春期过渡期的生理标志物 (SA 1.)，建立 青少年发病 T2D 发展的社会和行为风险因素和保护因素 已经建立的（SA 2.），并评估遗传和表观遗传数据以进一步 对青年疾病发病机制的机械理解（SA 3.）。最终，这项工作将支持 更好地了解哪些人有患青年型 T2D 的风险并进行识别 从糖尿病前期进展为 T2D 的决定因素，这将支持突破性的未来预防 这些方法一旦经过评估，就可以根据个人风险进行调整。

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.