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.

项目概要 二十多年来，通过本地和多中心研究，我们辛辛那提儿童医院的团队已经 记录了美国青年发病 2 型糖尿病 (T2D) 的流行病学及其相关的早发并发症 此外，最近的研究表明，目前的治疗方法并不能减缓或预防疾病的发生。 青年发病的 T2D 一旦开始就会进展，凸显了这种疾病的侵袭性本质以及 不幸的是，迄今为止的研究未能得出足够数量的青少年。 已经发展为 T2D，限制了定义谁处于危险之中以及潜在的病理生理学的能力。 开发了一项前瞻性、纵向观察队列研究以及一系列假设驱动的研究 旨在揭示导致青年发病的 T2D 病理生理学的调查，直接解决总体问题 我们建议招募一批根据风险因素进行选择的年轻人。 该队列将进行与 2 型糖尿病的发展相关的胰腺β的详细研究。 (β) 细胞功能，包括胰岛素敏感性和分泌的测量，这些研究将与这些研究相结合。 评估遗传、肥胖、代谢因素、行为和心理社会风险，以阐明这些风险如何 影响 β 细胞功能和进展为 T2D 的因素监测队列中青少年的比例。 发展 T2D 且相关合并症的频率将实现目标 1，同时评估 β 细胞功能 青春期期间，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 细胞功能的作用来实现 辛辛那提儿童医院在 T2D 方面拥有长期、经过验证的临床和研究专业知识。 儿童肥胖和青年发病的 2 型糖尿病以及进行胰腺 β- 复杂研究的经验 细胞功能，包括频繁采样的静脉内葡萄糖耐量测试、钳夹研究和口服葡萄糖 我们的网站还拥有大量种族/民族、城市/农村和社会经济的患者。 多样化的临床队列，具有在我们之前 NIH 资助的研究中招募和留住参与者的能力， 我们已经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。 U01 联盟的合作伙伴，以增进我们对青年发病 T2D 病理生理学的理解。 该提案将完善 T2D 风险最高的青少年的表型，并确定影响 β 细胞的因素 功能和 T2D 的进展 这将使联盟能够制定有针对性的干预措施来预防。 下一步是青年发病的 T2D。