Understanding and Targeting the Pathophysiology of Youth-onset Type2 Diabetes

儿童2型糖尿病（T2D）具有侵袭性病因，具有大量的短期和长期并发症。 健康并发症和医疗费用。迫切需要：（1）查明儿童和青少年的身份， 最高风险; 2）识别可改变的影响因素; 3）了解潜在的病理生理学;以及，4） 确定这些因素在性别和种族/民族之间的差异。全面和整体的理解， 这些问题需要开发模型，可以确定个别因素和敏感的时间窗口， T2D转换需要全国性的努力和多学科联盟。我们提议担任 在拟议的NIDDK联盟内运营的15个临床中心将招募和跟踪一个国家 儿童队列（估计值= 3，750）代表了T2D风险儿科人群的多样性。我们 多学科团队在儿童肥胖和糖尿病的纵向研究方面拥有广泛的专业知识，包括 NIDDK资助的一项为期15年的纵向研究（R01 DK 59211; PI：Goran），对300名拉丁美洲人进行了随访 儿童T2D风险，导致近100篇出版物。从这项研究和其他先前的研究中，我们发现 需要一个更大和更多样化的群体，纳入环境暴露，并纳入 全面的营养、代谢和社会决定因素。在我们的网站上，我们将招募250名参与者 患有肥胖症和2型糖尿病家族史，每两年进行一次评估。我们将与利益相关者和其他 联盟网站，以优化招聘和保留。我们提出了三种互补的方法来评估 2型糖尿病的代谢基础：来自口服葡萄糖耐量试验的胰岛素分泌、清除和β细胞功能 频繁采样;血红蛋白A1c和持续葡萄糖监测范围内的时间百分比。我们将 监测代谢和环境因素的测量：1）全身脂肪，内脏和皮下脂肪 通过DEXA和MRI检测腹部脂肪组织、肝脏和胰腺脂肪; 2）生化标志物（游离脂肪 酸、性类固醇、脂质、炎症特征、肠促胰岛素和肝酶）; 3）生活方式（饮食、睡眠和 身体活动）; 4）暴露于干扰内分泌的化学品和空气污染; 5）社会决定因素 健康此外，我们建议收集生物样本（如DNA，粪便，唾液），以建立一个生物库， 未来的调查我们将与该联盟合作制定统一的协议和协调的结果 措施我们假设：1）患有T2D的儿童在青春期β细胞功能会有更大的下降， 和葡萄糖时间范围减少，这将与整体肥胖的增加有关， 肝脏脂肪，与未患T2D的儿童相比，这些关系在性别和年龄上会有所不同。 种族; 2）高膳食糖，获得健康食品的机会有限，以及全氟烷基暴露较高 物质和/或空气污染物也与T2D风险有关。通过利用这种力量 财团，我们还建议开发一个结构化的风险评分分析，以表征不同的内型， 暴露和风险因素，可预测青春期发育期间进展为T2D。

Type 2 diabetes (T2D) in childhood has an aggressive etiology, with substantial short- and long-term health complications and medical costs. There is an urgent need to: 1) identify children and adolescents at highest risk; 2) identify modifiable contributing factors; 3) understand the underlying pathophysiology; and, 4) determine how these factors vary across sex and race/ethnicity. A comprehensive and holistic understanding of these issues is required to develop models that can identify individual factors and susceptible time windows for T2D conversion and requires a nationwide effort and multidisciplinary consortium. We propose to serve as 1 of the 15 Clinical Centers operating within the proposed NIDDK consortium that will recruit and track a national cohort of children (estimate = 3,750) representing the diversity of the pediatric population at risk for T2D. Our multidisciplinary team has extensive expertise in longitudinal studies of obesity and diabetes in children, including an NIDDK-funded 15-year longitudinal study (R01 DK 59211; PI: Goran) that followed a cohort of 300 Latino children at risk for T2D, resulting in almost 100 publications. From this and other prior studies, we have identified the need for a larger and more diverse cohort, incorporation of environmental exposures, and inclusion of comprehensive nutritional, metabolic, and social determinants. At our site, we will recruit 250 participants with obesity and family history of T2D with bi-annual assessments. We will work with stakeholders and other consortium sites to optimize recruitment and retention. We propose three complementary approaches to assess the metabolic basis of T2D: insulin secretion, clearance, and β-cell function from an oral glucose tolerance test with frequent sampling; hemoglobin A1c, and percent time in range from continuous glucose monitoring. We will monitor metabolic and environmental factors by measuring: 1) total body fat, visceral and subcutaneous abdominal adipose tissue, and liver and pancreatic fat by DEXA and MRI; 2) biochemical markers (free fatty acids, sex steroids, lipids, inflammatory profiles, incretins, and liver enzymes); 3) lifestyle (diet, sleep, and physical activity); 4) exposure to endocrine-disrupting chemicals and air pollution; 5) social determinants of health. In addition, we propose collection of biological samples (eg DNA, stool, saliva) to create a biobank for future investigation. We will work with the consortium to develop a unified protocol and harmonized outcome measures. We hypothesize: 1) Children who develop T2D will have a greater pubertal decline in β-cell function, and decreased glucose time-in-range, which will be associated with greater increase in overall adiposity and liver fat, compared to children who do not develop T2D, and that these relationships will differ across sex and ethnicity; and, 2) High dietary sugar, limited access to healthy foods, and higher exposure to perfluoroalkyl substances and/or air pollutants will also be associated with risk of T2D. Through harnessing the power of this consortium, we also propose development of a structured risk score analysis to characterize different endotypes, exposures and risk factors that predict progression to T2D during pubertal development.