Study to Investigate the Pathophysiology of Type 2 Diabetes in Youth

青年 2 型糖尿病病理生理学研究

基本信息

批准号：
8694059
负责人：
SONIA CAPRIO
金额：
$ 36.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-22 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694059
关键词：
ADAMTS9 gene Address Adolescent Adult Affect Alleles Anti-Inflammatory Agents Anti-inflammatory Area Basic Science Beta Cell Bioinformatics Biological Markers Biopsy Categories Cell physiology Cell secretion Child Childhood Clinical Sciences Complex Defect Development Diabetes Mellitus Diagnosis Disease Dyslipidemias Environment Epidemiology Europe Failure Fatty Liver Fatty acid glycerol esters Financial compensation Functional disorder Funding Genes Genetic Genetic Determinism Genetic Polymorphism Genotype Glucose Glucose Intolerance Goals Grant Hepatic Hereditary Disease Individual Inflammatory Insulin Insulin Resistance Investigation Lead Link Lipids Liver Longitudinal Studies Magnetic Resonance Imaging Measures Metabolism Modeling Muscle Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Oral PPARG gene Patients Pediatrics Peripheral Phenotype Physiological Population Prediabetes syndrome Predisposition Preventive Process Progress Reports Race Request for Proposals Research Risk Role Science of genetics Scientist Secondary to Series Single Nucleotide Polymorphism Staging Steatohepatitis Susceptibility Gene TCF7L2 gene TNF gene Testing Time Variant Visceral Youth abdominal fat adiponectin blood glucose regulation carbohydrate metabolism cohort coping diabetes risk endophenotype falls genetic variant genome wide association study glucagon-like peptide 1 glucose metabolism glucose tolerance impaired glucose tolerance indexing insulin secretion insulin sensitivity intrahepatic non-alcoholic fatty liver non-diabetic nonalcoholic steatohepatitis obesity in children prevent risk variant rosiglitazone subcutaneous success

项目摘要

DESCRIPTION (provided by applicant): This proposal requests renewed funding to continue our productive investigations on the Pathophysiology of Type 2 Diabetes in Youth. During the previous cycle we studied the role of insulin resistance and beta-cell secretion in the earliest stage of T2DM, namely: Impaired Glucose Tolerance (IGT). Recent studies by our group have established a strong relationship between fatty liver, prediabetes and T2DM in obese adolescents. Of note, our group has described the longitudinal trajectories in both insulin resistance, beta-cell function and Disposition Index during the transition from NGT to IGT, over a 3 year period in obese adolescents. We found that those who progressed to IGT already had pre-existing defects in beta-cell glucose responsivity at baseline (by the Oral Minimal Model). This series of studies led to our central hypothesis that prior to the onset of IGT or T2DM in youth, inherent genetic variants might be linked to beta-cell dysfunction which will worsen over a relatively short period of time due to the worsening of insulin resistance secondary to the accumulation of lipids in muscle and liver (NAFLD/NASH). Accordingly, we propose to search for genetic determinants of beta-cell defects that we have identified, using detailed phenotyping combined with genotyping of polymorphisms (SNPs) related to beta-cell function. To accomplish this goal we have created an interdisciplinary team of world-renowned scientists at Yale, and in Europe, spanning the breadth from Clinical science (Pediatrics, Epidemiology) and Basic science (Genetics, Bioinformatics). The specific aims are: Aim 1: A) To examine the relationships between a panel of 16 gene variants (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, HHEX, CDC123/CAMK1D, WFS1, TSPAN8/LGR5, THADA, ADAMTS9) and measures of beta-cell function in obese adolescents with a wide distribution of the DI, using the Oral Minimal Model. B) To longitudinally test the individual and cumulative effects of diabetes risks alleles on measures of beta-cell function in non- diabetic obese adolescents across the spectrum of DI, using the Oral Minimal Model. Aim 2: A) To determine longitudinally whether adiponectin (total and/or HMW) is associated with hepatic fat accumulation determined by Fast-MRI. B) To determine if circulating adiponectin levels, total and/or the HMW form, distinguish simple hepatic steatosis from steatohepatitis (NASH), and whether it might act as a biomarker of NASH, determined by biopsy. Ultimately, the results of this project will be crucial in attaining our long term goals of (a) understanding the fundamental causes(s) of T2DM in youth and (b) developing strategies to predict and prevent the disease and its complications.

描述（由申请人提供）：该提案要求续签资金继续我们对青年2型糖尿病的病理生理学的生产性调查。在上一个周期中，我们研究了胰岛素抵抗和β细胞分泌在T2DM最早阶段的作用，即：葡萄糖耐受性受损（IGT）。我们小组的最新研究已经在肥胖青少年中建立了脂肪肝，前糖尿病和T2DM之间的牢固关系。值得注意的是，我们的小组在肥胖青少年的3年期间，在从NGT到IGT的过渡期间描述了胰岛素抵抗，β细胞功能和处置指数中的纵向轨迹。我们发现，发展到IGT的人已经在基线时（通过口服最小模型）在β细胞葡萄糖响应中存在预先存在的缺陷。这一系列研究导致了我们的中心假设，即在年轻人中IGT或T2DM发作之前，固有的遗传变异可能与β细胞功能障碍有关，由于胰岛素抵抗的恶化，这会在相对较短的时间内恶化脂质在肌肉和肝脏中的积累（NAFLD/NASH）。因此，我们建议搜索我们已经鉴定出的β细胞缺陷的遗传决定因素，并使用与β细胞功能有关的详细表型结合了多态性（SNP）的基因分型。为了实现这一目标，我们在耶鲁大学和欧洲建立了一个由世界知名科学家组成的跨学科团队，涵盖了临床科学（儿科，流行病学）和基础科学（遗传学，生物信息学）的广度。 The specific aims are: Aim 1: A) To examine the relationships between a panel of 16 gene variants (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, HHEX, CDC123/CAMK1D, WFS1, TSPAN8/LGR5，THADA，ADAMTS9）以及使用口服最小模型的肥胖青少年中具有广泛分布的肥胖青少年的β细胞功能的度量。 b）使用口服最小模型，纵向测试糖尿病的个体和累积效应对跨DI频谱的非糖尿病肥胖青少年的β细胞功能的度量。目标2：a）纵向确定脂联素（总和/或HMW）是否与快速MRI确定的肝脂肪积累有关。 b）确定循环脂联素水平，总和/或HMW形式是否将简单的肝脂肪变性与脂肪性肝炎（NASH）区分开，以及它是否可以用作活检确定的NASH的生物标志物。最终，该项目的结果对于（a）了解青年中T2DM的基本原因以及（b）制定策略来预测和预防疾病及其并发症的策略至关重要。