Pathogenesis of youth onset pre-diabetes and Type 2 diabetes

青年发病的糖尿病前期和2型糖尿病的发病机制

• 批准号: 10361972
• 负责人: SONIA CAPRIO
• 金额: $ 76.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361972
• 关键词: Adolescent obesity; Adult; Affect; Aftercare; Alleles; Beta Cell; Body Composition; Cell physiology; Clinical Trials Design; Closure by clamp; Coupled; Data; Diabetes Mellitus; Disease Progression; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Funding; Genetic; Glucagon; Glucose; Glucose Clamp; Glycerol; Grant; Health; Hepatic; Impairment; Insulin; Insulin Resistance; Islet Cell; Lipolysis; Liver Fibrosis; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Measures; Metabolic Diseases; Metabolic syndrome; Minor; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Oral; Pathogenesis; Pediatrics; Placebos; Prediabetes syndrome; Predisposition; Prevalence; Protons; Randomized; Research Design; Risk; Role; Safety; Series; System; TCF7L2 gene; Techniques; Testing; Translational Research; Triglycerides; Variant; Withdrawal; Work; Youth; abdominal fat; active method; analog; arm; base; blood glucose regulation; cohort; density; functional improvement; glucagon-like peptide 1; glucose production; glucose tolerance; impaired glucose tolerance; improved; in vivo; innovation; insight; insulin sensitivity; intrahepatic; intravenous glucose tolerance test; islet; lipid biosynthesis; liraglutide; liver imaging; metabolic abnormality assessment; mimetics; multi-ethnic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel strategies; pediatric non-alcoholic fatty liver disease; preservation; prevent; stable isotope

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.

项目总结 TODAY和RISE的研究显示，β细胞功能迅速下降，对两种 儿科治疗T2D最常用的治疗方法。这种可怕的情况因经济增长而进一步恶化。 非酒精性脂肪性肝病(NAFLD)的患病率影响到美国约40%的肥胖青年。因此，在这里 迫切需要有效的方法来保护β细胞的功能，减少肥胖青年的非酒精性脂肪肝 以防止疾病的发展。探讨胰岛素抵抗、胰岛β细胞功能障碍和 NAFLD在T2D：糖耐量受损(IGT)的最早阶段，我们形成了两个大型多民族队列： 青年起病糖尿病的发病机制研究(NCT01967849)和耶鲁大学儿科 NAFLD/NASH队列(NCT01966627)。在使用这些队列的一系列研究中，我们发现β细胞 肥胖青年的与胰岛素敏感性相关的功能随着2小时血糖水平和 肝脏脂肪变性的程度。重要的是，在当前的赠款周期中，我们确定了肥胖青年的关键作用 在糖调节失调和NAFLD的病理生理学早期，INT效应降低。加在一起， 这些研究为使用新的方法来理解 胰岛β细胞功能障碍、胰岛素系统受损和非酒精性脂肪肝发病之间的相互联系 糖尿病前期。我们的主要目标是：确定利拉鲁肽，第一个GLP-1 类似物可能通过检测其对β细胞和α细胞功能以及肝脏的影响来恢复血糖稳态 肥胖青年糖耐量低减和NAFLD/NASH的脂肪含量具体的目的和假设(H)就是目的 1和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 将测试利拉鲁肽(Victoza 1.8 mg)为期6个月(6-M)的治疗是否改善？细胞功能和 与安慰剂相比，降低胰高血糖素水平；B：是否改善了？细胞功能 青年肥胖合并糖耐量低减患者停药后可持续6-M积极治疗3-M 和NAFLD/NASH。目的2和H2：A：测试利拉鲁肽6-M治疗是否降低MRI-PDFF 与安慰剂相比，通过新脂肪生成(DNL)的变化测量肝脏脂肪变性，以及B：是否 在3M冲洗期后，这种影响仍然存在。C：探讨利拉鲁肽抗肝纤维化的疗效 治疗6个月后行磁共振弹性成像(MRE)测量。整体方法：我们的团队 将使用一种创新的研究设计，结合严格和详细的肝脏MRI成像，加上 钳制技术和稳定同位素的使用以深入了解利拉鲁肽可能的作用机制 影响与胰岛素敏感性相关的β细胞功能，减少青年糖耐量低减患者的肝内脂肪积聚 和非酒精性脂肪肝。总的来说，拟议的机械性随机对照试验研究将提供重要的概念验证、安全性 资料和提高对两种高发肝内胆汁淤积症的发病机制和治疗的认识 儿科代谢紊乱：糖耐量受损和NAFLD/NASH。