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

• 批准号: 7887332
• 负责人: SONIA CAPRIO
• 金额: $ 37.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/7887332
• 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; Genetic Variation; Genotype; Glucose; Glucose Intolerance; Goals; Grant; Hepatic; Hereditary Disease; Individual; Inflammatory; Insulin; Insulin Resistance; Investigation; Lead; Link; Lipids; Liver; Longitudinal Studies; 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; 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; public health relevance; rosiglitazone; subcutaneous; success

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. PUBLIC HEALTH RELEVANCE: Type 2 Diabetes in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT) and hepatic steatosis. Importantly, obese adolescents with IGT have pre-existing defect in insulin secretion. We will determine here if genetic factors are associated with defects in insulin secretion in a large cohort of obese children and adolescents and assess if the simple measure of circulating adiponectin may function as a biomarker of hepatic fat accumulation. Our long term goal is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide us towards better preventive and treatment avenues.

描述（由申请人提供）：该提案要求重新提供资金，以继续我们对青年 2 型糖尿病病理生理学的富有成效的研究。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 早期阶段（即：葡萄糖耐量受损 (IGT)）中的作用。我们小组最近的研究表明，肥胖青少年的脂肪肝、糖尿病前期和 T2DM 之间存在密切关系。值得注意的是，我们的小组描述了肥胖青少年在 3 年多的时间里从 NGT 过渡到 IGT 期间胰岛素抵抗、β 细胞功能和处置指数的纵向轨迹。我们发现，那些进展为 IGT 的人在基线时已经存在 β 细胞葡萄糖反应性缺陷（通过口服最小模型）。这一系列研究得出了我们的中心假设，即在青少年出现 IGT 或 T2DM 之前，固有的遗传变异可能与 β 细胞功能障碍有关，由于继发性胰岛素抵抗恶化，β 细胞功能障碍会在相对较短的时间内恶化。肌肉和肝脏中脂质的积累（NAFLD/NASH）。因此，我们建议使用详细的表型分析结合与 β 细胞功能相关的多态性 (SNP) 基因分型来寻找我们已识别的 β 细胞缺陷的遗传决定因素。为了实现这一目标，我们在耶鲁大学和欧洲组建了一支由世界知名科学家组成的跨学科团队，涵盖临床科学（儿科、流行病学）和基础科学（遗传学、生物信息学）。具体目标是： 目标 1：A) 检查一组 16 个基因变体（TCF7L2、PPARG、FTO、KCNJ11、NOTCH2、WFS1、CDKAL1、IGF2BP2、SLC30A8、JAZF1、HHEX、CDC123/CAMK1D、WFS1、 TSPAN8/LGR5、THADA、ADAMTS9) 和措施使用口腔最小模型研究 DI 分布广泛的肥胖青少年的 β 细胞功能。 B) 使用口腔最小模型，纵向测试糖尿病风险等位基因对整个 DI 范围内的非糖尿病肥胖青少年的 β 细胞功能测量的个体和累积影响。目标 2：A) 纵向确定脂联素（总脂联素和/或 HMW）是否与快速 MRI 测定的肝脏脂肪积累相关。 B) 确定循环脂联素水平、总脂联素水平和/或 HMW 形式，区分单纯性肝脂肪变性和脂肪性肝炎 (NASH)，以及通过活检确定它是否可以作为 NASH 的生物标志物。最终，该项目的结果对于实现我们的长期目标至关重要：(a) 了解青少年 T2DM 的根本原因；(b) 制定预测和预防该疾病及其并发症的策略。 公众健康相关性：肥胖青年患 2 型糖尿病之前通常会出现糖尿病前期状态，称为：葡萄糖耐量受损 (IGT) 和肝脂肪变性。重要的是，患有 IGT 的肥胖青少年预先存在胰岛素分泌缺陷。我们将在这里确定遗传因素是否与一大群肥胖儿童和青少年的胰岛素分泌缺陷有关，并评估循环脂联素的简单测量是否可以作为肝脏脂肪积累的生物标志物。我们的长期目标是生成有关青少年 2 型糖尿病的遗传学和病理生理学的信息，这最终可能会指导我们找到更好的预防和治疗途径。