Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes-Texas Children's Center.

了解并针对青年发病 2 型糖尿病的病理生理学 - 德克萨斯儿童中心。

• 批准号: 10583407
• 负责人: FIDA BACHA
• 金额: $ 5.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2029-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583407
• 关键词: 19 year old; Adult; Age; Algorithms; Behavioral; Beta Cell; Biochemical; Black race; Body Composition; Body fat; Catecholamines; Cell physiology; Child; Childhood; Clinical; Collaborations; Collection; Communities; Complex; Conceptions; County; DNA Methylation; Deposition; Deterioration; Development; Diagnosis; Disease; Disease Outcome; Dual-Energy X-Ray Absorptiometry; Early identification; Enrollment; Ensure; Environmental Risk Factor; Epigenetic Process; Equilibrium; Evolution; Failure; Family; Fatty acid glycerol esters; Functional disorder; Genetic; Gestational Diabetes; Goals; Gonadal Steroid Hormones; Growth Factor; Growth and Development function; Health Insurance; Health Surveys; Hepatic; Hispanic; Hormonal; Hormones; Hydrocortisone; Individual; Inflammation; Insulin Resistance; Intervention; Investigation; Knowledge; Latino; Longitudinal Surveys; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Methodology; Methylation; Mission; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; OGTT; Obesity; Onset of illness; Organ; Pathogenesis; Pathway interactions; Pediatric Hospitals; Phenotype; Physiological; Population; Prediabetes syndrome; Predisposing Factor; Predisposition; Prevalence; Prevention; Process; Puberty; Research Design; Research Infrastructure; Research Personnel; Resources; Risk; Risk Factors; Standardization; Stress; Surveys; Texas; United States National Institutes of Health; Variant; Visceral fat; Youth; abdominal fat; adverse childhood events; clinical center; clinical phenotype; cohort; comorbidity; design; diabetes pathogenesis; disease phenotype; disorder risk; epigenetic marker; epigenetic regulation; ethnic diversity; ethnic minority; falls; federal poverty level; glucose tolerance; glycemic control; health determinants; high risk; hypothalamic-pituitary-adrenal axis; improved; indexing; innovation; insight; insulin secretion; insulin sensitivity; inter-individual variation; maternal obesity; member; multidisciplinary; novel; patient population; peripheral blood; personalized intervention; predicting response; prediction algorithm; predictive modeling; prevent; progression risk; puberty transition; racial minority; recruit; risk prediction; risk stratification; social; social factors; social health determinants; stem; success; treatment strategy; urinary

Project Summary Youth-onset type 2 diabetes (T2D) is a heterogeneous disease, more rapidly progressive than adult-onset disease, and is associated with increased comorbidities. Yet, it is not clear which high-risk youth will eventually progress to T2D. T2D pathogenesis is related to complex hormonal mechanisms that result in β-cell dysfunction, influenced by genetic, epigenetic, social and environmental factors. The overarching goal of this proposal is to prevent youth-onset T2D. Our aims are to identify the risk factors and pathophysiologic changes that lead to the development of youth-onset T2D. We will collaborate as a member of a consortium of clinical centers to achieve these aims. We will leverage our community and stakeholders’ engagement, our robust research infrastructure and the diverse high-risk patient population at our Center, to recruit a high-risk diverse cohort of children from early through mid-puberty (age range 8 to 14 years, Tanner stage II-IV at enrollment), with normal glucose tolerance and with prediabetes. We will screen 300 children aiming to retain 200 children longitudinally, perform in-depth assessments and survey them for the progression to T2D. We will investigate complementary pathways which, by disrupting the delicate balance between insulin sensitivity and secretion, are most likely to modulate the risk of progression to T2D in youth. To that end, we will 1) characterize the evolution of β-cell dysfunction in relation to changes in adiposity, sex steroids and growth factors during the pubertal transition. We will combine clinical phenotypes with physiologic measures of glucose tolerance, β-cell function and insulin sensitivity (derived from serial oral glucose tolerance tests), circulating metabolites, body composition and abdominal fat changes (dual-energy X-ray absorptiometry and magnetic resonance imaging); 2) employ novel epigenetic markers of DNA methylation at correlated regions of systemic interindividual variation (CoRSIVs) to evaluate epigenetic changes that may predispose to β-cell dysfunction; and 3) evaluate social and behavioral determinants of health that could lead to long-term disease phenotype through promotion of adiposity and activation of the hypothalamic-pituitary-adrenal axis (as measured by urinary catecholamines and cortisol), and inflammation pathways. Our innovative study design will allow us to determine the evolution of the risk factors for youth-onset T2D during the pubertal transition, the underlying metabolic changes, and the modifying social and environmental effects, in the context of genetic/epigenetic susceptibility. The findings from this study are highly significant to improve the identification of high-risk children vulnerable to progression to T2D, and characterize the pathophysiology of the disease during a critical window of childhood growth and development. The knowledge gained will allow the consortium to develop risk stratification algorithms and design personalized precision interventions, to prevent youth-onset T2D.

项目概要 青年发病的 2 型糖尿病 (T2D) 是一种异质性疾病，比成人发病的进展更快 疾病，并与合并症增加有关。然而，尚不清楚哪些高危青少年最终会 进展至 T2D。 T2D 发病机制与导致 β 细胞功能障碍的复杂激素机制有关， 受遗传、表观遗传、社会和环境因素的影响。该提案的总体目标是 预防青少年发病的 T2D。我们的目标是确定导致该疾病的危险因素和病理生理变化 青年发病的 T2D 的发展。我们将作为临床中心联盟的成员进行合作，以实现 这些目标。我们将利用我们的社区和利益相关者的参与以及我们强大的研究基础设施 以及我们中心的多样化高危患者群体，从不同的地区招募高危多样化儿童群体 青春期早期至中期（年龄范围 8 至 14 岁，入组时 Tanner II-IV 期），血糖正常 耐受性和糖尿病前期。我们将筛选300名儿童，旨在纵向保留200名儿童，执行 深入评估并调查其是否进展为 T2D。我们将研究互补途径 通过破坏胰岛素敏感性和分泌之间的微妙平衡，最有可能调节 青少年进展为 T2D 的风险。为此，我们将 1）描述 β 细胞功能障碍的演变 与青春期过渡期间肥胖、性类固醇和生长因子的变化有关。我们将结合 临床表型与葡萄糖耐量、β细胞功能和胰岛素敏感性的生理测量（衍生 来自系列口服葡萄糖耐量测试）、循环代谢物、身体成分和腹部脂肪变化 （双能X射线吸收测定法和磁共振成像）； 2）采用新的表观遗传标记 系统个体间变异 (CoRSIV) 相关区域的 DNA 甲基化用于评估表观遗传 可能导致 β 细胞功能障碍的变化； 3）评估健康的社会和行为决定因素 这可能会通过促进肥胖和激活 下丘脑-垂体-肾上腺轴（通过尿儿茶酚胺和皮质醇测量）和炎症 途径。我们的创新研究设计将使我们能够确定青少年发病风险因素的演变 青春期过渡期间的 T2D、潜在的代谢变化以及社会和环境的改变 环境影响，在遗传/表观遗传易感性的背景下。这项研究的结果非常 对于提高对容易进展为 T2D 的高危儿童的识别具有重要意义，并表征 儿童生长发育关键时期疾病的病理生理学。这 所获得的知识将使联盟能够开发风险分层算法并设计个性化的 精准干预，预防青少年发病的 T2D。