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

摘要 估计表明，在短短16年（2001-2017年）的时间里，青年T2 D的患病率翻了一番， 从每1000名青年中0.34人的估计患病率降至每1000名青年中0.67人。通过我们在 青年糖尿病研究（2012年）我们报告称，T2 D的发病率为 在边缘化的种族和少数民族群体中，美国印第安人和 非西班牙裔黑人青年经历T2 D的最大负担。我们已经证明了- 成人型T2 D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、动脉僵硬和高血压在青年发作的T2 D中加速发作。 虽然已经确定超重和肥胖以及家族史与肥胖有关， 青年发病T2 D的风险增加，大多数具有这些风险因素的青年不会发病 2型糖尿病T2 D很少发生在青春期开始之前，并且已经确定青春期与 胰岛素敏感性降低，通常在坦纳III期达到最低点，然后恢复到治疗前水平 健康青少年青春期坦纳V期水平。年轻人似乎面临着最大的风险， T2 D的发展，因为他们向青春期后期的进展。我们提出了一个纵向队列 一项旨在提供青春期过渡期病理生理标志物的深层表型分析的研究， 肥胖的高危青年，评估这些因素与未充分探索的社会，行为和早期 青年T2 D发展的生命危险因素。作为支持该联盟的众多临床研究中心之一，我们 准备招募504名青年，他们来自高度多样化的肥胖青年人群，年龄在早期到中期， 青春期（坦纳阶段II或III）。业务目标包括招募和留住一批多样化的高危人群， 青年（OA 1），保持利益相关者参与，在整个研究规划过程中为研究提供信息， 实施和传播（OA 2），并建立一个参与者标本和样本生物库 可从中进行未来的辅助研究（OA 3）。这些支持的科学目标 业务目标涉及对青年进行深入的表型表征的总体目标， T2 D发作，包括评估青春期过渡期的生理标志物（SA 1.），建立 青年发病T2 D的社会和行为风险因素以及保护因素， 已经建立的（SA 2.），并评估遗传和表观遗传数据， 对青年疾病发病机理的机械理解（SA 3.）。最终，这项工作将支持 提高对哪些个体有发生青年发病型T2 D风险的认识，并允许识别 从前驱糖尿病进展到T2 D的决定因素，这将支持未来突破性的预防 一旦评估，就可以针对个人风险调整方法。

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.