Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes

摘要： 2型糖尿病（T2 D）在青年降低生活质量和年。T2 D的差异在生命早期出现， 对低收入和少数民族青年的影响尤为严重。T2 D是复杂过程的结果， 生物易感性和相互依赖的社会，行为和环境因素，代表了根源 差距的原因。肥胖、胰岛素抵抗和胰腺β细胞功能障碍一直是许多人关注的焦点。 旨在了解青年T2 D病理生理学的临床研究。然而，多种因素直接 并间接导致风险，包括不健康的行为，青春期，遗传易感性，和表观遗传 调变这些额外的因素受到社会和环境背景的影响， 我们认为这有助于我们进一步了解高危人群中的T2 D。我们的跨学科团队 在弱势群体和代表性不足的人群中了解、预防和管理T2 D的丰富经验 青年十多年来，我们的研究一直由一个社区咨询委员会指导，该委员会已告知 NIH资助的多项研究集中在脆弱人群中的T2 D。我们对T2 D研究的总体方法 在考虑文化、环境和社会因素的扩展生态发展模型中构建 在关键的生命阶段影响个人健康行为和健康结果的环境。我们将应用 这种模式和杠杆高容量儿科内分泌的做法，位于全国最大的之一， 整合儿科医疗保健系统，招募肥胖和前驱糖尿病青年的多样化样本。到 为了进一步支持这项工作，我们制定了一项强有力的社区参与战略，以确保 研究扩展了现有的科学，并在当地社区实现健康公平。我们 跨学科小组非常适合为一个查明高危青年的国家联合会作出贡献， 了解T2 D的病理生理学，并最终改善这一人群的健康。 在此背景下，我们提出以下具体目标： 具体目标1：入组、表型和前瞻性随访6000例种族多样性队列（400例/研究中心） 8-14岁肥胖和糖尿病前期儿童。 具体目标2：整合自由生活评估的行为和健康行为。 具体目标3：记录导致T2 D风险的家庭、社会和环境条件。 具体目标4：采集和储存空腹血液样本，以支持基因组和代谢组学分析， 验证和发现方法。 具体目标5：检查生物、行为和社会的个体和潜在的相互作用效应 T2 D风险的决定因素。

ABSTRACT: Type 2 diabetes (T2D) in youth reduces quality and years of life. Disparities in T2D emerge early in life and disproportionately impact low-income and minority youth. T2D is the result of complex processes involving biological susceptibility and interdependent social, behavioral, and environmental factors that represent the root causes of disparities. Obesity, insulin resistance and pancreatic β-cell dysfunction have been the focus of many clinical studies aimed at understanding the pathophysiology of T2D in youth. However, multiple factors directly and indirectly contribute to risk including unhealthy behaviors, puberty, genetic predisposition, and epigenetic modulation. These additional factors are influenced by the social and environmental context that must but considered to advance our understanding of T2D in high-risk populations. Our transdisciplinary team has extensive experience understanding, preventing, and managing T2D among vulnerable and underrepresented youth. For over a decade, our research has been guided by a Community Advisory Board that has informed multiple NIH-funded studies focused on T2D in vulnerable populations. Our overall approach to T2D research is framed within an Expanded Ecodevelopmental Model that considers cultural, environmental, and social contexts that influence individual health behaviors and health outcomes during critical life periods. We will apply this model and leverage high-volume pediatric endocrine practice situated within one of the nation’s largest integrated pediatric healthcare systems to recruit a diverse sample of youth with obesity and prediabetes. To further support this work, we have developed a robust community engagement strategy to ensure that the research extends the available science AND advances towards health equity in the local community. Our transdisciplinary team is well-suited to contribute to a national consortium that identifies high-risk youth, understands the pathophysiology of T2D, and ultimately improves the health of this population. With this context, we propose the following Specific Aims: Specific Aim 1: Enroll, phenotype, and prospectively follow an ethnically diverse cohort of 6000 (400/site) children ages 8-14 with obesity and prediabetes. Specific Aim 2: Integrate free living assessments of glycemia and health behaviors. Specific Aim 3: Document family, social and environmental conditions that contribute to T2D risk. Specific Aim 4: Collect and bank fasting blood samples to support genomic and metabolomic analyses using validation and discovery approaches. Specific Aim 5: Examine the individual and potential interactive effects of biological, behavioral, and social determinants of T2D risk.