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:
  • 金额:
    $ 76.4万
  • 依托单位:
  • 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

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.
项目总结

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:
  • 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。
Identification of a novel link between adiposity and visuospatial perception.
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SONIA CAPRIO其他文献

SONIA CAPRIO的其他文献

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{{ truncateString('SONIA CAPRIO', 18)}}的其他基金

Neurocognition in youth with prediabetes
糖尿病前期青少年的神经认知
  • 批准号:
    10413361
  • 财政年份:
    2017
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neurocognition in youth with prediabetes
糖尿病前期青少年的神经认知
  • 批准号:
    9767116
  • 财政年份:
    2017
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neurocognition in youth with prediabetes
糖尿病前期青少年的神经认知
  • 批准号:
    10224174
  • 财政年份:
    2017
  • 资助金额:
    $ 76.4万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 76.4万
  • 项目类别:
Pathogenesis of youth onset pre diabetes and Type 2 diabetes.
青年发病前糖尿病和 2 型糖尿病的发病机制。
  • 批准号:
    9257738
  • 财政年份:
    2016
  • 资助金额:
    $ 76.4万
  • 项目类别:
Pathogenesis of youth onset pre diabetes and Type 2 diabetes.
青年发病前糖尿病和 2 型糖尿病的发病机制。
  • 批准号:
    10006541
  • 财政年份:
    2016
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neural Functioning of Feeding Centers in Obese Youth
肥胖青少年喂养中心的神经功能
  • 批准号:
    8610296
  • 财政年份:
    2010
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neural Functioning of Feeding Centers in Obese Youth
肥胖青少年喂养中心的神经功能
  • 批准号:
    7790484
  • 财政年份:
    2010
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neural Functioning of Feeding Centers in Obese Youth
肥胖青少年喂养中心的神经功能
  • 批准号:
    8228168
  • 财政年份:
    2010
  • 资助金额:
    $ 76.4万
  • 项目类别:
Neural Functioning of Feeding Centers in Obese Youth
肥胖青少年喂养中心的神经功能
  • 批准号:
    8050152
  • 财政年份:
    2010
  • 资助金额:
    $ 76.4万
  • 项目类别:

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