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

项目总结 二十多年来，我们辛辛那提儿童医院的团队通过本地和多中心的研究， 记录了美国青年发病的2型糖尿病(T2D)的流行病学及其相关的早发性共同发病 病态和并发症。此外，最近的研究表明，目前的治疗方法并不能减缓或预防 青年发病的T2D一旦开始，就会进展，突出这种情况的侵袭性和 对预防的迫切需要。不幸的是，到目前为止，研究还没有发现足够数量的年轻人 已经发展出T2D，限制了定义谁处于危险之中和潜在的病理生理学的能力。因此，我们 开发了一项前瞻性的纵向观察队列研究以及一系列假设驱动 调查揭示导致青年起病的T2D的病理生理学直接解决主要问题 此次U01融资机会的目标。我们建议招募一批年轻人，他们是根据风险因素挑选出来的 与2型糖尿病的发展有关。这个队列将对胰岛β进行详细的研究。 (β)细胞功能，包括测量胰岛素敏感性和分泌。这些研究将与 对遗传、肥胖、代谢因素、行为和心理社会风险的评估，以阐明这些因素是如何 影响β细胞功能和向T2D进展的因素。监测队列中年轻人的比例 发展T2D和相关并存的频率将实现目标1，同时评估β-细胞功能 在青春期和与β细胞功能相关的遗传、代谢和激素因素将完成目标 2.目标3，将通过评估行为和心理社会因素对β-细胞功能和 进展到T2D。辛辛那提儿童医院拥有长期、成熟的临床和研究专业知识 儿童肥胖和青年起病的2型糖尿病，以及进行复杂的胰腺β研究的经验 细胞功能包括频繁采样的静脉葡萄糖耐量试验、钳夹试验和口服葡萄糖 耐受性测试。我们的网站也有大量的种族/民族、城市/农村和社会经济方面的患者。 不同的临床队列证明有能力招募和留住我们之前NIH资助的研究的参与者， 我们成功地在许多儿科多中心研究中进行了合作。因此，我们处于有利地位，可以 U01联盟的合作伙伴，以促进我们对青年发病的T2D的病理生理学的理解。这 该提案将完善T2D最高风险青年的表型，并确定影响β-细胞的因素 功能和向T2D的进展。这将使该财团能够制定有针对性的干预措施，以防止 下一步是以青年为起点的T2D。

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.