What Activates Type 2 diabetes in Children (WATCH)

项目摘要 肥胖和随后的2型糖尿病（T2 D）在青少年中越来越常见，但肥胖的表型和糖尿病的发病率在青少年中越来越高。 青年型T2 D（YO-T2 D）与成人不同。我们帮助领导的NIDDK TODAY研究表明， 2型糖尿病青年患者口服药物的失败率高（> 50%）且快速，需要更快的胰岛素治疗 vs.在ADOPT研究中接受相似持续时间治疗的成人。作为进一步的证据，在我们的NIDDK RISE研究中， 其中葡萄糖耐量受损（IGT）或新诊断的T2 D青年的治疗反应是 与BMI和初始BMI相似的成年人相比，青年人的胰岛素抵抗是成年人的两倍 与给予相同剂量的成年人相比， 类似的药物治疗。最后，在我们的HIP研究中，二甲双胍没有改善胰岛素 即使在青春期早期开始的血糖正常的肥胖青年中， 创新方法。最令人关注的是，今天证明了微血管糖尿病的发病率 平均年龄仅为26.4±2.8岁，并发症发生率为32-68%，影响了本应在 他们的生产力高峰;并发症更严重地影响了那些少数种族/民族，提高 与健康差距有关的问题。这种前所未有的早期发病率和预计的医疗保健费用 要求重点定义a）青年B）病理生理学的理想T2 D诊断和/或筛查标准 Y-T2 D和成人型T2 D之间的区别c）如何预防Y-T2 D d）如何更好地治疗Y-T2 D一次 礼物虽然发展Y-T2 D的一些风险因素（例如家族史，肥胖等）是公认的， 这些高危青年中只有一小部分在青少年时期发展为T2 D。因此，其他因果成分 需要探讨的问题，如不良的童年经历，压力，贫困，种族主义，睡眠/昼夜节律， 久坐行为的细微差异，以及青春期激素的确切影响。我们建议 招募并纵向随访3，540名不同年龄段的青少年（236名来自我们的研究中心），这些青少年有从城市发展为T2 D的风险 和青春期早期的农村地区，每6个月进行一次纵向评估（HbA 1c， Taneda量表，每6个月一次，OGTT/DXA/MRI，每年一次）与额外的样本储存配对进行一次分析 积累了患有新发T2 D的青年的“临界质量”。我们提出以下具体目标， 与我们的利益相关者/社区成员合作开发， T2 D的影响：1。为了评估代谢和青春期事件的变化模式，我们将测量： 胰岛素敏感性/分泌、身体组成、自由生活行为和青春期激素以及银行 血液粪便毛发和尿液2.为了评估心理社会和心理因素，我们将测量压力， 歧视、戏弄、微攻击、社会地位、获得护理、抑郁/焦虑和皮质醇。3.到 使用目标1和2中收集的数据，并应用无偏数据分析方法来识别生物标志物 并开发一个预测模型，预测谁将发展Y-T2 D。

PROJECT SUMMARY Obesity and subsequently type 2 diabetes (T2D) is increasingly common in adolescents, but the phenotype of youth-onset T2D (YO-T2D) differs from adults. The NIDDK TODAY study we helped lead, demonstrated that youth with T2D had a high (≈50%) and rapid failure rate on oral medications and faster need for insulin therapy vs. adults treated for a similar duration in the ADOPT study. As further evidence, in our NIDDK RISE study, where treatment responses in youth with impaired glucose tolerance (IGT) or newly diagnosed T2D were directly compared to adults of similar BMI and initial glycemia, youth were twice as insulin resistant as adults and had rapid deterioration of β-cell function and glycemic control compared to adults given the same treatment with similar medication adherence. Finally in our HIP study, metformin did not improve insulin sensitivity or secretion even when started early in puberty in normoglycemic youth with obesity, arguing for innovative approaches. Of most concern, TODAY demonstrated an incidence of microvascular diabetes complications ranging from 32-68% by a mean age of only 26.4±2.8 yrs, affecting individuals who should be at their peak of productivity; complications more heavily affected those with minority race/ethnicity, raising concerns related to health disparities. This unprecedented early morbidity and projected health care costs mandate a focus on defining a) the ideal T2D diagnostic and/or screening criteria for youth b) pathophysiologic distinctions between Y-T2D and adult-onset T2D c) how to prevent Y-T2D d) how to better treat Y-T2D once present. Though some risk factors for developing Y-T2D (e.g. family history, obesity, etc.) are well-established, only a small subset of these high-risk youth progress to T2D as adolescents. Thus, other causal components need to be explored, such as adverse childhood experiences, stress, poverty, racism, sleep/circadian rhythm, subtle differences within sedentary behavior, and the exact impact(s) of pubertal hormones. We propose to enroll and follow longitudinally 3,540 diverse youth (236 from our site) at risk for developing T2D from urban and rural locations who are early in puberty, and perform longitudinal assessments every 6 mo (HbA1c, Taneda scale every 6 mo, OGTT/DXA/MRI, yearly) paired with additional sample storage to be analyzed once a “critical mass” of youth with new-onset T2D is accumulated. We propose the following Specific Aims, developed in collaboration with our stakeholders/community members from populations disproportionately affected by T2D: 1. To assess patterns of change in metabolic and pubertal events, we will measure: glycemia, insulin sensitivity/secretion, body composition, free living behaviors, and pubertal hormones, as well as bank blood, stool, hair, and urine. 2. To assess psychosocial and psychological factors, we will measure stress, discrimination, teasing, microaggressions, social status, access to care, depression/anxiety, and cortisol. 3. To use the data collected in Aims 1 and 2 and apply unbiased data analysis methodology to identify biomarkers for progression risk and develop a prediction model for who will develop Y-T2D.