Cincinnati Children's Clinical Center for Targeting the Pathophysiology of Youth-Onset Type 2 Diabetes

项目摘要 二十多年来，通过当地和多中心研究，我们在辛辛那提儿童医院的团队 记录了美国青年发病的2型糖尿病（T2 D）的流行病学及其相关的早发性并发症， 发病率和并发症。此外，最近的研究表明，目前的疗法并不能减缓或阻止 一旦开始，青年发病的T2 D的进展，突出了这种疾病的侵袭性， 迫切需要预防。不幸的是，迄今为止的研究未能产生足够数量的年轻人， 已经发展为T2 D，限制了确定谁处于风险和潜在病理生理学的能力。因此我们 我开发了一项前瞻性、纵向观察性队列研究，沿着一系列假设驱动 研究揭示导致青年发病T2 D的病理生理学，直接解决 U 01融资机会的目标。我们建议招募一批年轻人， 与2型糖尿病的发展有关。该队列将接受胰腺β-淀粉样蛋白的详细研究， （β）细胞功能，包括胰岛素敏感性和分泌的测量。这些研究将与 评估遗传、肥胖、代谢因素、行为和心理社会风险，以阐明这些风险是如何产生的。 影响β细胞功能和进展为T2 D的因素。监测青年群体中 发生T2 D，相关合并症的频率将满足目标1，同时评估β细胞功能 在青春期，与β细胞功能相关的遗传、代谢和激素因素将完成目的 2.目标3，将通过评估行为和心理社会因素对β细胞功能的作用来实现， 进展为T2 D。辛辛那提儿童医院在以下方面拥有长期的、经过验证的临床和研究专长： 儿童肥胖和青年发病的2型糖尿病，并有进行复杂的胰腺β- 细胞功能，包括频繁采样的静脉葡萄糖耐量试验、钳夹研究和口服葡萄糖 公差测试我们的研究中心也有大量的种族/民族、城市/农村和社会经济的患者 在我们之前的NIH资助的研究中，有记录的招募和留住参与者的能力的不同临床队列， 我们在许多儿科多中心研究中成功合作。因此，我们处于有利地位， U 01联盟的合作伙伴，以促进我们对青年发病T2 D的病理生理学的理解。这 一项提案将细化T2 D风险最大的青年人的表型，并确定影响β细胞的因素。 功能和进展为T2 D。这将使该联盟能够制定有针对性的干预措施， 青年型2型糖尿病作为下一步。

PROJECT SUMMARY For more than two decades through local and multi-center studies our team at Cincinnati Children’s Hospital has documented the epidemiology of youth-onset type 2 diabetes (T2D) in the US and its associated early-onset co- morbidities and complications. Furthermore, recent studies show current therapies do not slow or prevent the progression of youth-onset T2D once it has started, highlighting the aggressive nature of this condition and the critical need for prevention. Unfortunately, studies to date have failed to yield a sufficient number of youths who have developed T2D, limiting the ability to define who is at risk and the underlying pathophysiology. As such, we have developed a prospective, longitudinal observational cohort study along with a series of hypothesis driven investigations to uncover the pathophysiology leading to youth-onset T2D directly addressing the overarching objective of this U01 funding opportunity. We propose to recruit a cohort of youth, selected for risk factors associated with the development of type 2 diabetes. This cohort will undergo detailed studies of pancreatic beta (β) cell function that include measures of insulin sensitivity and secretion. These studies will be coupled with assessment of genetics, adiposity, metabolic factors, behavioral and psychosocial risks to elucidate how these factors influence β-cell function and progression to T2D. Monitoring the proportion of youth in the cohort who develop T2D and the frequency of associated co-morbidities will fulfill Aim 1, while assessing β-cell function during puberty and the genetic, metabolic and hormonal factors associated with β-cell function will complete Aim 2. Aim 3, will be achieved by evaluating the role of behavioral and psychosocial factors on β-cell function and progression to T2D. Cincinnati Children’s Hospital has longstanding, proven clinical and research expertise in pediatric obesity and youth-onset type 2 diabetes and experience performing complex studies of pancreatic β- cell function including frequently sampled intravenous glucose tolerance testing, clamp studies, and oral glucose tolerance testing. Our site also has high patient volumes of race/ethnicity, urban/rural, and socioeconomic diverse clinical cohorts with documented ability to recruit and retain participants in our prior NIH funded studies, and we have successfully collaborated in many pediatric multicenter studies. Thus, we are well positioned to partner in this U01 consortium to advance our understanding of the pathophysiology to youth-onset T2D. This proposal will refine the phenotype of youth at greatest risk for T2D and identify factors that influence β-cell function and the progression to T2D. This will position the consortium to develop targeted interventions to prevent youth-onset T2D as a next step.