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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：
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。