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

项目摘要 青年起病的2型糖尿病(T2D)是一种异质性疾病，比成人起病进展更快 疾病，并与增加的合并症有关。然而，目前还不清楚哪些高危青年最终会 到T2D的进展。T2D的发病机制与导致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。这项提议的首要目标是 预防青春期T2D。我们的目标是确定导致高血压的危险因素和病理生理变化。 青春期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，我们强大的研究基础设施 和我们中心多样化的高危患者群体，招募来自以下人群的高危多样化儿童 青春期早期至中期(8至14岁，注册时为Tanner II-IV期)，血糖正常 耐受性和糖尿病前期。我们将筛查300名儿童，目标是纵向保留200名儿童，表演 深入评估并对他们进行调查，以便向T2D发展。我们将研究互补的途径 它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 青年发展为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、性激素和生长因子变化的关系。我们将联合起来 临床表型，包括糖耐量、β细胞功能和胰岛素敏感性的生理指标(衍生 来自一系列口服葡萄糖耐量试验)、循环代谢产物、身体成分和腹部脂肪的变化 (双能X射线吸收和磁共振成像)；2)使用新的表观遗传标记 系统个体间变异相关区域DNA甲基化(CoRSIVs)评估表观遗传学 可能导致β细胞功能障碍的变化；以及3)评估健康的社会和行为决定因素 这可能通过促进肥胖和激活细胞外基质而导致长期的疾病表型 下丘脑-垂体-肾上腺轴(尿儿茶酚胺和皮质醇测定)和炎症 小路。我们创新的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，以及修改的社会和 环境影响，在遗传/表观遗传易感性的背景下。这项研究的发现是高度 改善易发展为T2D的高危儿童的识别和特征具有重要意义 儿童生长发育关键时期疾病的病理生理学。这个 所获得的知识将使该联盟能够开发风险分层算法并设计个性化 精准干预，预防青少年发病的T2D。

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.