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

辛辛那提儿童临床中心针对青年发病 2 型糖尿病的病理生理学

• 批准号: 10583296
• 负责人: AMY SANGHAVI SHAH
• 金额: $ 7.03万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2029-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583296
• 关键词: Address; Adolescent; Age; Anxiety; Behavior; Behavioral; Beta Cell; COVID-19 pandemic; Cell physiology; Cells; Cessation of life; Characteristics; Child; Childhood; Chronic; Clinical; Closure by clamp; Collaborations; Complex; Coupled; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Dyslipidemias; Epidemiology; Ethnic Origin; Exposure to; Failure; Frequencies; Functional disorder; Funding; Funding Opportunities; Future; Genetic; Genetic Risk; Geography; Goals; Health; Hormonal; Hypertension; Incidence; Intervention; Investigation; Knowledge; Literature; Longitudinal Studies; Measures; Mental Depression; Metabolic; Monitor; Multicenter Studies; Natural History; Nature; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Pancreas; Patients; Pediatric Hospitals; Phenotype; Physical activity; Polycystic Ovary Syndrome; Positioning Attribute; Prevention; Prospective Studies; Psychosocial Factor; Puberty; Race; Recording of previous events; Research; Risk; Risk Factors; Role; Rural; SARS-CoV-2 infection; Sampling; Second Degree Relative; Secondary to; Series; Sex Differences; Site; Sleep; Stress; Structure of beta Cell of islet; Testing; Time; United States; United States National Institutes of Health; Work; Youth; adipokines; clinical center; cohort; comorbidity; design; early onset; ethnic difference; experience; fatty liver disease; indexing; inflammatory marker; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; obesity in children; observational cohort study; participant retention; physical inactivity; prenatal exposure; prevent; prospective; psychosocial; racial difference; recruit; response; risk selection; sex; socioeconomics

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.

项目摘要 二十多年来，通过本地和多中心研究，我们的辛辛那提儿童医院的团队拥有 记录了美国及其相关的早期发作的2型糖尿病（T2D）的流行病学 病毒和并发症。此外，最近的研究表明，当前疗法不会放慢或阻止 一旦开始，青年发出的T2D的发展，强调了这种疾病的侵略性和 预防的关键需求。不幸的是，迄今为止的研究未能产生足够数量的年轻人 已经开发了T2D，限制了定义谁处于危险和潜在的病理生理学的能力。因此，我们 已经开发了一项前瞻性的，纵向的观察队列研究以及一系列假设驱动 揭示导致青年发作T2D的病理生理学的调查直接解决了总体 U01资金机会的目标。我们建议招募一系列青年队，并被选为风险因素 与2型糖尿病的发展有关。该队列将对胰腺β的详细研究进行详细研究 （β）包括测量胰岛素敏感性和分泌的细胞功能。这些研究将与 评估遗传学，肥胖，代谢因素，行为和社会心理风险，以阐明这些风险 因素影响β细胞的功能和发展为T2D。监视队列中青年的比例 开发T2D和相关的合并症的频率将实现AIM 1，同时评估β细胞功能 在青春期以及与β细胞功能相关的遗传，代谢因素和骑马因子期间将完成AIM 2. AIM 3将通过评估行为和社会心理因素对β细胞功能的作用以及 发展为T2D。辛辛那提儿童医院拥有长期以来的，经过验证的临床和研究专业知识 小儿肥胖和2型糖尿病的青年肥胖和胰腺β-进行复杂研究的经验 细胞功能包括经常采样静脉葡萄糖耐量测试，夹紧研究和口服葡萄糖 公差测试。我们的网站还拥有大量的种族/种族，城市/农村和社会经济 潜水员临床人群具有招募和保留参与者的能力，我们先前的NIH资助研究， 我们已经成功地在许多儿科多中心研究中进行了合作。那我们有很好的位置 在这个U01联盟中的合作伙伴，以提高我们对病理生理学的理解到青年发作的T2D。这 提案将完善青年的表型，最大的T2D风险并确定影响β细胞的因素 功能和对T2D的进展。这将定位财团以制定有针对性的干预措施以防止 下一步。