Pathogenesis of youth onset pre-diabetes and Type 2 diabetes

项目摘要 TODAY和RISE研究揭示了β细胞功能的快速下降及其对两种免疫抑制剂的无反应性。 最常用的儿科T2 D治疗方法。这种可怕的情况进一步加剧了上升的 非酒精性脂肪性肝病（NAFLD）的患病率影响美国约40%的肥胖青年。因此， 目前迫切需要有效的方法来保护β细胞功能，减少肥胖青年的NAFLD， 以防止疾病进展。研究胰岛素抵抗、β细胞功能障碍和 T2 D早期阶段的NAFLD：糖耐量受损（IGT），我们形成了2个大型多种族队列： 青少年糖尿病发病机制（PYOD）研究（NCT 01967849）和耶鲁儿科 NAFLD/NASH队列（NCT 01966627）。在一系列使用这些队列的研究中，我们发现β细胞 随着2小时血糖水平的升高，肥胖青年的胰岛素敏感性功能逐渐降低， 肝脏脂肪变性的程度。重要的是，在当前的资助周期中，我们确定了肥胖青年的关键作用， 在葡萄糖调节异常和NAFLD的病理生理学早期，肠促胰岛素的作用降低。综合起来看， 这些研究为使用新的方法来理解 β-细胞功能障碍、肠促胰岛素系统受损和NAFLD之间的相互联系 糖尿病前期我们的主要目的是：确定利拉鲁肽，第一个GLP-1， 类似物，可能通过检查其对胰岛细胞和α细胞功能以及肝脏的影响来恢复葡萄糖稳态。 IGT和NAFLD/NASH肥胖青年的脂肪含量。具体目标和假设（H）是目标 1&H1：A：采用随机、双盲、安慰剂对照、平行组临床试验设计（RCT），我们 将检测利拉鲁肽（诺和力1.8 mg）治疗6个月（6个月）是否可改善胰岛细胞功能， 与安慰剂相比，降低胰高血糖素水平，和B：β细胞功能的功能改善是否 IGT肥胖青年停药后，6个月的积极治疗可持续3个月 NAFLD/NASH目的2&H2：A：测试利拉鲁肽6-M治疗是否会降低MRI-PDFF 通过新生脂肪生成（DNL）的变化，与安慰剂相比测量的肝脂肪变性，和B：是否 在3个月的洗脱期后，效果仍然存在。C：探讨利拉鲁肽减轻肝纤维化的疗效 治疗6个月后通过磁共振弹性成像（MRE）测量。整体方法：我们的团队 将采用创新的研究设计，结合严格和详细的肝脏MRI成像， 钳夹技术和稳定同位素的使用，以深入了解利拉鲁肽可能 影响与胰岛素敏感性相关的β细胞功能，并减少IGT青年的肝内脂肪堆积 和NAFLD。总的来说，拟议的机制RCT研究将提供重要的概念验证、安全性 数据和推进我们对两种高度流行的肝内型糖尿病的发病机制和治疗的理解， 儿科代谢紊乱：葡萄糖耐量受损和NAFLD/NASH。

PROJECT SUMMARY The TODAY and RISE studies revealed a rapid decline in β-cell function and its unresponsiveness to two of the most commonly used treatments for T2D in pediatrics. This dire scenario is further aggravated by the rising prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) affecting ~40% of obese youth in the US. Hence, there is a pressing need for effective approaches to preserve β-cell function and reduce NAFLD in obese youth, in order to prevent disease progression. To investigate the roles of insulin resistance, beta-cell dysfunction, and NAFLD in the earliest stage of T2D: Impaired Glucose Tolerance (IGT), we formed 2 large multiethnic cohorts: The Pathogenesis of Youth Onset Diabetes (PYOD) study (NCT01967849), and The Yale Pediatric NAFLD/NASH Cohort (NCT01966627). In a series of studies using these cohorts, we found that beta-cell function relative to insulin sensitivity gradually decreases in obese youth across rising 2-hr glucose levels and degrees of Hepatic Steatosis. Importantly, in the current grant cycle, we identified in obese youth the key role of a reduced incretin effect early in the pathophysiology of glucose dysregulation and NAFLD. Taken together, these studies provide a strong scientific premise for using novel approaches to understand the interconnectedness among beta-cell dysfunction, impaired incretin system, and NAFLD in the onset of prediabetes. Our Primary Objective is: To determine the mechanisms by which Liraglutide, the first GLP-1 analogue, might restore glucose homeostasis by examining its effects on ß-cell and alfa cell function and hepatic fat content in obese youth with IGT and NAFLD/NASH. The Specific Aims and Hypotheses (H) are Aim 1&H1: A: Using a randomized, double-blind, placebo-controlled, parallel-group, clinical trial design (RCT), we will test whether a 6-month (6-M) treatment with Liraglutide, (Victoza 1.8 mg) improves ß-cell function and decreases glucagon levels, compared to placebo, and B: whether the functional improvements in ß-cell function following 6-M of active treatment can be sustained 3-M after the withdrawal of therapy in obese youth with IGT and NAFLD/NASH. Aim 2&H2: A: To test whether a 6-M treatment with Liraglutide decreases MRI-PDFF measured hepatic steatosis compared to placebo, via changes in de Novo Lipogenesis (DNL), and B: whether the effects persist after a 3-M washout period. C: To explore the efficacy of Liraglutide in reducing hepatic fibrosis measured by Magnetic Resonance Elastography (MRE) after 6-M of treatment. Overall Approach: Our team will use an innovative study design that incorporates rigorous and detailed MRI imaging of the liver, coupled with clamp-techniques and the use of stable isotopes to gain insights into the mechanisms by which Liraglutide might affect beta-cell function relative to insulin sensitivity and reduce intrahepatic fat accumulation in youth with IGT and NAFLD. Collectively, the proposed mechanistic RCT study, will provide important proof-of-concept, safety data and advance our understanding of the pathogenesis and treatment of two highly prevalent endo-hepatic metabolic disorders in pediatrics: Impaired glucose tolerance and NAFLD/NASH.