What Activates Type 2 diabetes in Children (WATCH)

项目总结 肥胖和随后的2型糖尿病(T2D)在青少年中越来越常见，但 青春期T2D(Yo-T2D)不同于成人。我们帮助领导的NIDDK今日研究证明 患有T2D的年轻人口服药物失败率高(≈50%)且失败率快，需要胰岛素治疗的速度更快 与在收养研究中接受类似持续时间治疗的成年人进行比较。作为进一步的证据，在我们的NIDDK Rise研究中， 在患有糖耐量低减(IGT)或新诊断的T2D的年轻人中，治疗反应是 与体重指数和初始血糖相似的成年人相比，年轻人的胰岛素抵抗能力是成年人的两倍 与给予相同剂量的成年人相比，β细胞功能和血糖控制迅速恶化 用药依从性相似的治疗。最后，在我们的髋关节研究中，二甲双胍并没有改善胰岛素 在患有肥胖的血糖正常的年轻人中，即使在青春期早期就开始敏感或分泌，也认为 创新方法。最令人关注的是，今天显示了微血管糖尿病的发病率 并发症从32%到68%不等，平均年龄仅为26.4±2.8岁，影响本应在 他们的生产力达到顶峰；并发症对少数族裔的影响更大，提高了 与健康差距有关的关切。这种史无前例的早期发病率和预计的医疗成本 任务重点是定义a)理想的青少年T2D诊断和/或筛查标准b)病理生理学 Y-T2D与成人起病的T2D的区别c)如何预防Y-T2D d)如何更好地治疗一次Y-T2D 现在时。尽管Y-T2D的一些危险因素(如家族史、肥胖等)都是老牌的， 这些高危青年中只有一小部分人在青少年时期发展为T2D。因此，其他因果成分 需要探讨的问题，如不良童年经历、压力、贫困、种族主义、睡眠/昼夜节律、 久坐行为的细微差别以及青春期荷尔蒙的确切影响(S)。我们建议 注册并纵向跟踪3,540名不同类型的年轻人(来自我们网站的236名)，这些年轻人有可能从城市发展为T2D 和青春期早期的农村地区，每6个月进行一次纵向评估(HbA1c， Taneda每6个月测量一次，OGTT/DXA/MRI，每年)与额外的样品存储配对，只需分析一次 新发的T2D的青年人群已经达到了“临界值”。我们提出了以下具体目标， 与我们的利益相关者/来自不成比例的人口的社区成员合作开发 受T2D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：血糖， 胰岛素敏感性/分泌、身体成分、自由生活行为、青春期激素以及银行 血、大便、头发和尿液。2.为了评估心理社会和心理因素，我们将测量压力， 歧视、取笑、微侵略性、社会地位、获得护理的机会、抑郁/焦虑和皮质醇。3.至 使用AIMS 1和AIMS 2中收集的数据，并应用无偏见的数据分析方法来识别生物标志物 对于进展风险，并开发谁将发展为Y-T2D的预测模型。

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.