Understanding the Pathophysiology of Type 2 Diabetes in Navajo Youth

项目摘要 2型糖尿病（T2 D）在美国和世界各地的青年中呈上升趋势，并且不成比例地影响种族 以及包括美洲印第安人在内的少数民族人口。高危青少年人数持续增加 此外，儿童肥胖症也在流行，青春期出现T2 D的青少年比例前所未有。 这一趋势对公共卫生的影响是非常重要的，因为使人衰弱的并发症可能会 在成年早期，在生命中最活跃和最富有成效的几年里表现出来。预防 青年型T2 D至关重要，因为病程比典型的“成人型T2 D”更具侵袭性。然而 目前对青年发病T2 D的病理生理学的了解有限，因此仍不清楚针对谁或 如何预防青少年T2 D青春期是T2 D发展的关键时期，因为这个生命阶段是 以胰岛素敏感性的显著变化为特征，并不总是在青春期结束时消退。之前 研究主要采用横断面或病例对照设计，或纵向协议，很少跨越 青春期的持续时间，排除了一个整体的综合如何纵向模式的变化，生物标志物的 葡萄糖-胰岛素稳态在青年发病的T2 D中达到顶峰。破译导致青春期发病的途径 T2 D是了解临床前疾病进展的基础，这有可能直接告知 有针对性的预防措施。通过RFA-DK-21-002，NIDDK寻求建立一个青春期早期队列 青年T2 D风险，以更好地了解青年发病T2 D的病理生理学。我们在此建议， 科罗拉多|纳瓦霍临床站点将为该联盟招募400名居住在农村的美国印第安青年， 青年发病T2 D风险最高的亚组。在科罗拉多大学的领导下，该临床研究中心 我们将在纳瓦霍族的一个农村社区开展青年糖尿病研究 自2000年以来我们将招募青春期早期（坦纳2-3期）的青少年，这些青少年发病风险较高， 基于超重或肥胖状态（BMI ≥第85百分位数）和美国印第安人自我认同的T2 D 比赛参与者将被随访33个月，平均每年进行2小时口服葡萄糖耐量试验 测试（每名参与者n= 3-4）和每半年一次的访视（每名参与者n= 3-4），以收集额外的 生物样本和与T2 D风险相关的生理、行为、家族和心理社会因素的数据。 我们的具体目标是：1）在当地招募400名青春期早期（坦纳期）的美国印第安青年 2-3)超重或肥胖，并纵向跟踪他们以评估T2 D的风险; 2）在整个财团中， 确定葡萄糖-胰岛素体内平衡生物标志物的变化模式，这些变化在青年发展中达到顶峰- 发病T2 D;和3）在整个联盟，开发青年发病T2 D的预测模型，并确定亚 年轻发病T2 D的表型。

PROJECT ABSTRACT Type 2 diabetes (T2D) is on the rise among youth in the US and worldwide, and disproportionately affects racial and ethnic minority populations including American Indians. The number of at-risk youth continues to increase alongside the child obesity epidemic, with an unprecedented proportion of youth developing T2D during puberty. The public health implications of this trend are highly significant, as debilitating complications are likely to manifest by early adulthood during what should be the most active and productive years of life. Prevention of youth-onset T2D is crucial as the course of disease is more aggressive than the typical “adult-onset T2D”. Yet current knowledge of the pathophysiology of youth-onset T2D is limited, so it is still unclear whom to target or how to prevent youth-onset T2D. Puberty is a critical period for T2D development, as this life stage is characterized by marked changes in insulin sensitivity that do not always resolve by the end of puberty. Prior studies largely used cross-sectional or case-control designs, or longitudinal protocols that rarely spanned the duration of puberty, precluding a holistic synthesis of how longitudinal patterns of change in biomarkers of glucose-insulin homeostasis culminate in youth-onset T2D. Deciphering the pathways leading to youth-onset T2D is fundamental to understanding pre-clinical disease progression, which has potential to directly inform targeted prevention approaches. With RFA-DK-21-002, the NIDDK seeks to establish a cohort of early pubertal youth at risk for T2D to better understand the pathophysiology of youth-onset T2D. We propose here a Colorado|Navajo clinical site that will recruit for this consortium 400 rural-dwelling American Indian youth, the subgroup at highest risk for youth-onset T2D. Under leadership from the University of Colorado, this clinical site will be based in a rural community on the Navajo Nation where we have conducted youth diabetes research since 2000. We will enroll youth in early puberty (Tanner Stages 2-3) who have elevated risk for youth-onset T2D based on overweight or obesity status (BMI ≥85th percentile) and self-identification with American Indian race. Participants will be followed for 33 months, on average, undergoing annual 2-hour oral glucose tolerance tests (n= 3-4 per participant) and semi-annual visits (n= 3-4 per participant) for collection of additional biospecimens and data on physiological, behavioral, familial, and psychosocial factors associated with T2D risk. Our specific aims are: 1) locally, recruit 400 American Indian youth in the early stages of puberty (Tanner stage 2-3) with overweight or obesity, and follow them longitudinally to assess the risk of T2D; 2) across the consortium, identify patterns of change in biomarkers of glucose-insulin homeostasis that culminate in development of youth- onset T2D; and 3) across the consortium, develop prediction models for youth-onset T2D and identify sub- phenotypes of incident youth-onset T2D.