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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要今天和崛起的研究表明，β细胞功能迅速下降及其对两个小儿T2D的最常用治疗方法。这种可怕的场景被上升进一步汇总非酒精性脂肪肝疾病（NAFLD）的患病率影响了美国肥胖的40％。因此，那里迫切需要有效的方法来保留β细胞功能并减少肥胖青年的NAFLD，为了防止疾病进展。研究胰岛素抵抗，β细胞功能障碍和 NAFLD处于T2D最早的阶段：葡萄糖耐受性受损（IGT），我们形成了2个大型多种族同伙：青年发病糖尿病（PYOD）研究（NCT01967849）和耶鲁小儿的发病机理 NAFLD/NASH队列（NCT01966627）。在使用这些队列的一系列研究中，我们发现Beta细胞相对于胰岛素敏感性的功能逐渐降低2小时葡萄糖水平上升的肥胖青年肝脂肪变性程度。重要的是，在当前的赠款周期中，我们在肥胖青年中确定了关键作用在葡萄糖失调和NAFLD的病理生理学早期降低的增加效果的降低。在一起，这些研究为使用新颖的方法来了解 Beta细胞功能障碍，增加系统受损和NAFLD之间的互连性糖尿病。我们的主要目的是：确定利拉格肽（第一个GLP-1）的机制模拟，可能会通过检查其对ß细胞和阿尔法细胞功能的影响以及肝功能来恢复葡萄糖稳态 IGT和NAFLD/NASH的肥胖青年中的脂肪含量。具体目标和假设（H）是目标 1＆H1：A：使用随机，双盲，安慰剂对照，平行组，临床试验设计（RCT），我们将测试用Liraglutide进行6个月（6-M）的治疗，（Victoza 1.8 mg）可以改善ß细胞功能和与安慰剂相比，胰高血糖素水平降低，B：ß细胞功能的功能改善是否是否在肥胖的IGT肥胖年轻人撤离治疗后，可以在6米处进行活跃治疗3米。和NAFLD/NASH。 AIM 2＆H2：A：测试6-M Liraglutide治疗是否会降低MRI-PDFF 与安慰剂相比，测得的肝脂肪变性是通过Novo脂肪形成（DNL）的变化（DNL）和B：是否：是否：是否是效果在3米冲洗期间持续存在。 C：探索利拉格林在降低肝纤维化中的效率治疗6 m后，通过磁共振弹性弹力仪（MRE）测量。总体方法：我们的团队将使用创新的研究设计，该设计结合了严格而详细的MRI成像，并与夹具技术和使用稳定的同位素来了解Liraglutide可能的机制相对于胰岛素敏感性影响β细胞的功能，并降低IGT青年的肝内脂肪积累和nafld。拟议的机械RCT研究总的来说，将提供重要的概念证明数据并促进我们对两个高度普遍的内部肝脏的发病机理和治疗的理解儿科的代谢障碍：葡萄糖耐量受损和NAFLD/NASH。