Pathophysiology of Type 2 Diabetes in Youth

青年 2 型糖尿病的病理生理学

• 批准号: 7234848
• 负责人: SONIA CAPRIO
• 金额: $ 38.76万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234848
• 关键词: 2,4-thiazolidinedione; Acute; Address; Adipocytes; Adolescent; Affect; Arginine; Beta Cell; Cell physiology; Cell secretion; Child; Childhood; Clinic; Deltastab; Deposition; Deterioration; Development; Diabetes Mellitus; Disease Progression; Doctor of Medicine; Early identification; Enzymes; Evaluation; Fatty acid glycerol esters; Financial compensation; Functional disorder; Funding; Gastrointestinal Hormones; Glucose; Glucose Clamp; Glycerol; Grant; Health; Hepatic; High Prevalence; Hyperglycemia; Impairment; Inflammatory; Insulin; Insulin Resistance; Intervention Studies; Intra-abdominal; Investigation; Kinetics; Lipids; Liver; Liver diseases; Longitudinal Studies; Magnetic Resonance Imaging; Metabolic; Metabolic syndrome; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Peptides; Peripheral; Phenotype; Physiological; Plasma; Prevention; Reporting; Request for Proposals; Research; Research Personnel; Risk; Role; Sampling; Series; Skeletal Muscle; Staging; Stimulus; Thiazolidinediones; Visceral; Weight; Workplace; Youth; abdominal fat; adiponectin; base; blood glucose regulation; cardiovascular risk factor; cohort; cytokine; follow-up; glucagon-like peptide 1; glucose metabolism; glucose production; glucose tolerance; impaired glucose tolerance; improved; indexing; insight; insulin secretion; insulin sensitivity; intrahepatic; liver function; mathematical model; non-alcoholic fatty liver; prevent; response; rosiglitazone; stable isotope; subcutaneous

DESCRIPTION (provided by applicant): This proposal requests renewed funding to continue our investigations of the pathophysiology of type 2 diabetes (T2DM) in youth. During the previous cycle, we studied the role of insulin resistance and beta-cell secretion in youth with impaired glucose tolerance (IGT). These studies revealed: 1) A high prevalence in IGT and the metabolic syndrome in obese youth (NEJM 2002 and 2004); 2) Adolescents with IGT have profound peripheral insulin resistance associated with increased intramyocellular (IMCL) and visceral fat, beta-cell dysfunction, and low adiponectin levels (Lancet, 2003). 3) In only two years, 30% of the obese youth transitioned from IGT to T2DM. This new proposal represents the natural progression of our research into the health effects of childhood obesity by addressing mechanisms related to the development of IGT. The specific aims are: 1) To determine whether treatment of obese adolescents with IGT with Rosiglitazone will restore normal glucose tolerance by improving insulin sensitivity and affecting lipid deposition. 2) To determine whether inadequate beta-cell compensation to insulin resistance is present in obese subjects with normal glucose tolerance. To unmask early beta-cell dysfunction, we will assess insulin secretion in response to different stimuli (hyperglycemia, GLP-1, and arginine) and use mathematical modeling of c-peptide to determine insulin secretion in a selected sample of obese subjects with a high vs. a low Disposition Index. 3) To characterize the metabolic phenotype of obese subjects presenting with Non-Alcoholic Fatty Liver Disease (high ALT) and compare them to weight-matched controls. We will also determine in a longitudinal study if NAFLD predates IGT in obese adolescents. To accomplish these aims, we will use glucose clamps, stable isotopes kinetics, and MRI and 1H-NMR imaging. The study proposed here will not only provide further insights in the pathophysiology of T2DM in obese youth but will serve as a template for a large intervention study for the prevention of T2DM in this group.

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（T2DM）病理生理学的调查。在上一个周期中，我们研究了胰岛素抵抗和β细胞分泌在葡萄糖耐量受损（IGT）中的作用。这些研究表明：1）肥胖青年的IGT和代谢综合征的高患病率（NEJM 2002和2004）； 2）患有IGT的青少年具有与增加的肌内细胞内（IMCL）和内脏脂肪，β细胞功能障碍以及低脂联素水平相关的深度外周胰岛素抵抗（Lancet，2003）。 3）在短短两年内，30％的肥胖青年从IGT过渡到T2DM。这项新的建议代表了我们通过解决与IGT发展有关的机制来研究我们对儿童肥胖症健康影响的自然发展。 具体目的是：1）确定用罗格列酮的IGT治疗肥胖的青少年是否会通过提高胰岛素敏感性和影响脂质沉积来恢复正常的葡萄糖耐受性。 2）确定是否在葡萄糖耐受性正常的肥胖受试者中是否存在β细胞抗胰岛素抵抗的补偿不足。为了揭示早期β细胞功能障碍，我们将评估胰岛素分泌，以响应不同的刺激（高血糖，GLP-1和精氨酸），并使用C肽的数学模型来确定具有较高的肥胖受试者样本的胰岛素分泌，该样本具有较高的发夹索引。 3）表征出肥胖受试者的代谢表型，这些受试者表现出非酒精性脂肪肝疾病（高ALT），并将其与体重匹配的对照进行比较。我们还将在纵向研究中确定肥胖青少年的IGT是否早于IGT。为了实现这些目标，我们将使用葡萄糖夹，稳定的同位素动力学以及MRI和1H-NMR成像。此处提出的研究不仅将为肥胖青年的T2DM病理生理提供进一步的见解，而且还将作为用于预防该组T2DM的大型干预研究的模板。