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

摘要 估计表明，在短短16年的时间里(2001-2017)，T2D在年轻人中的患病率翻了一番， 从估计的每1000名青年中有0.34名青年流行到每1000名青年中有0.67名青年。通过我们在 寻找青年糖尿病研究(SEARCH)我们报告了T2D的发病率是 在边缘化的种族和少数民族群体中有不成比例的经历，美国印第安人和 经历T2D最大负担的非西班牙裔黑人青年。我们已经证明了油井- 成人起病的T2D已知的并发症和并存，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起病的T2D中起病更快。 虽然超重和肥胖，再加上家族史，已经得到了很好的证实 青少年发病T2D的风险增加，大多数具有这些危险因素的青少年不会发展 T2D。T2D很少发生在青春期开始之前，众所周知，青春期与 胰岛素敏感性降低，通常在Tanner III期经历低谷，然后恢复到 健康青少年Tanner阶段V的青春期水平。年轻人似乎面临着最大的风险 随着他们进入青春期的后期阶段，T2D的发展。我们提出了一个纵向队列 这项研究旨在提供青春期过渡期间病理生理标志物的深入表型 肥胖的高危青年，评估这些因素与社会、行为和早期探索不足的关系 青少年T2D发生的生命危险因素。作为支持该联盟的众多临床网站之一，我们 准备招收504名青年，他们来自高度多样化的肥胖青年群体，年龄在2019年初到2019年中期 青春期(晒黑阶段II或III)。运营目标包括招募和留住不同的高危人群 青年(OA1)，在整个研究规划过程中保持利益相关者的参与，为研究提供信息， 实施和传播(OA2)，并建立参与者标本和样本生物库 可在此基础上进行未来的辅助研究(OA3)。它们所支持的科学目标 业务目标涉及对青年进行深入表型表征的首要目标-- 发作期T2D，包括青春期过渡期(SA 1)的生理标志物评估，建立 青少年发作性T2D的社会和行为危险因素及保护因素 已经建立的(SA 2)，并评估遗传和表观遗传学数据，以进一步 青年疾病发病机制的理解(SA 3.)。最终，这项工作将支持 更多地了解哪些人有患青春期T2D的风险，并允许识别 从糖尿病前期发展到T2D的决定因素，这将支持开创性的未来预防 一旦评估，就可以针对个人风险量身定做的方法。

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.