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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：
10688197
负责人：
SONIA CAPRIO
金额：
$ 76.4万
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 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688197
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 Fibrosis Functional disorder Funding Genetic Glucagon Glucose Glucose Clamp Glycerol Grant Health Hepatic Hyperinsulinism 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 Placebo Control 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 blood glucose regulation cohort density functional improvement glucagon-like peptide 1 glucose production glucose tolerance impaired glucose tolerance improved in vivo inflammatory milieu 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.

项目概要 TODAY 和 RISE 研究表明，β 细胞功能迅速下降，并且对其中两种药物无反应儿科最常用的 T2D 治疗方法。不断上升的房价进一步加剧了这种可怕的情况非酒精性脂肪肝 (NAFLD) 的患病率影响了美国约 40% 的肥胖青少年。因此，有迫切需要有效的方法来保护 β 细胞功能并减少肥胖青少年的 NAFLD，以防止疾病进展。研究胰岛素抵抗、β 细胞功能障碍和 NAFLD 在 T2D 的最早阶段：糖耐量受损 (IGT)，我们形成了 2 个大型多种族队列：青少年发病糖尿病 (PYOD) 的发病机制研究 (NCT01967849) 和耶鲁大学儿科 NAFLD/NASH 队列 (NCT01966627)。在使用这些队列进行的一系列研究中，我们发现 β 细胞随着 2 小时血糖水平的升高，肥胖青少年的胰岛素敏感性相关功能逐渐下降，并且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葡萄糖失调和 NAFLD 病理生理学早期肠促胰素效应降低的研究。综合起来，这些研究为使用新方法来理解 β细胞功能障碍、肠促胰岛素系统受损和 NAFLD 发病过程中的相互关联糖尿病前期。我们的主要目标是：确定第一个 GLP-1 利拉鲁肽的作用机制类似物，可能通过检查其对 β 细胞和阿尔法细胞功能以及肝脏的影响来恢复葡萄糖稳态患有 IGT 和 NAFLD/NASH 的肥胖青年的脂肪含量。具体目标和假设 (H) 是 Aim 1&H1：A：采用随机、双盲、安慰剂对照、平行组临床试验设计 (RCT)，我们将测试利拉鲁肽（Victoza 1.8 mg）为期 6 个月（6-M）的治疗是否可以改善 ß 细胞功能以及与安慰剂相比，胰高血糖素水平降低，B：β 细胞功能是否得到改善患有 IGT 的肥胖青少年在停止治疗后可维持 6-M 的积极治疗后 3-M 和 NAFLD/NASH。目标 2&H2：A：测试 6-M 利拉鲁肽治疗是否会降低 MRI-PDFF 与安慰剂相比，通过新脂肪生成 (DNL) 的变化测量肝脂肪变性，B：是否 3 分钟的冲洗期后，效果仍然存在。 C：探讨利拉鲁肽减轻肝纤维化的功效治疗 6 分钟后通过磁共振弹性成像 (MRE) 测量。总体方法：我们的团队将采用创新的研究设计，其中结合了严格而详细的肝脏 MRI 成像，再加上钳技术和使用稳定同位素来深入了解利拉鲁肽可能的机制影响与胰岛素敏感性相关的 β 细胞功能，并减少患有 IGT 的青少年肝内脂肪堆积和非酒精性脂肪性肝病。总的来说，拟议的机制 RCT 研究将提供重要的概念验证、安全性数据并加深我们对两种高度流行的肝内疾病发病机制和治疗的理解儿科代谢紊乱：糖耐量受损和 NAFLD/NASH。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantifying beta cell function in the preclinical stages of type 1 diabetes.

DOI：
10.1007/s00125-023-06011-5
发表时间：
2023-12
期刊：
DIABETOLOGIA
影响因子：
8.2
作者：
Galderisi, Alfonso;Carr, Alice L. J.;Martino, Mariangela;Taylor, Peter;Senior, Peter;Dayan, Colin
通讯作者：
Dayan, Colin

Adipose Tissue Insulin Resistance Is Not Associated With Changes in the Degree of Obesity in Children and Adolescents.

脂肪组织胰岛素抵抗与儿童和青少年肥胖程度的变化无关。