THE GLUCOSE TRANSPORT SYSTEM AND MECHANISMS OF HUMAN INSULIN RESISTANCE

葡萄糖转运系统和人体胰岛素抵抗机制

• 批准号: 7603186
• 负责人: W Timothy GARVEY
• 金额: $ 4.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603186
• 关键词: Admission activity; Biochemical; Biopsy; Blood; Blood Pressure; Body Composition; Calorimetry; Cardiovascular Diseases; Cell membrane; Cell surface; Computer Retrieval of Information on Scientific Projects Database; Consent; DEXA; Defect; Development; Electrocardiogram; Energy Metabolism; Fatty acid glycerol esters; Funding; GLUT4 gene; Genetic Determinism; Glucose Transporter; Grant; Hour; Human; Indirect Calorimetry; Individual; Inpatients; Institution; Insulin; Insulin Resistance; Intracellular translocation; Knowledge; Laboratories; Leg; Measurement; Mediating; Medical History; Molecular; Morbidity - disease rate; Muscle; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Physical Examination; Prevention strategy; Research; Research Personnel; Resistance; Resources; Scanning; Series; Skeletal Muscle; Societies; Soil; Source; Syndrome; System; Testing; Thigh structure; Time; United States National Institutes of Health; Urine; abdominal wall; base; day; diabetic; drug development; glucose metabolism; glucose tolerance; glucose transport; in vivo; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; lipid metabolism; metabolic abnormality assessment; mortality; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Insulin Resistance Syndrome provides the "common soil" for the development of Type 2 Diabetes Mellitus and Cardiovascular Disease. It is responsible for extensive morbidity and mortality in our society. The long-term objective is the necessity of finding the environmental and genetic determinants together with the biochemical or molecular basis of this insulin resistance. The knowledge will present new targets for drug development and will create rational approaches for preventive strategies. In NIDDM, insulin resistance is largely due to impaired stimulation of the glucose transport system in skeletal muscle; however, the molecular mechanisms have not been elucidated. Insulin stimulates glucose transport via translocation of intracellular GLUT4 glucose transporters to the cell surface. Insulin resistance in NIDDM is caused by profound depletion of GLUT4 in fat, while in muscle GLUT4 expression is normal, suggesting that GLUT4 translocation to the plasma membrane may be defective. The specific aim is to test the hypothesis that insulin resistance is due to defects in GLUT4 trafficking which impair insulin-mediated GLUT4 translocation in skeletal muscle. In order to accomplish this, it will be important to include healthy individuals along the insulin sensitive-resistant continuum as well as type 2 diabetics. Consented subjects will be admitted to the inpatient GCRC where a thorough medical history, physical examination, EKG, pre/post activity blood pressure measurements, and laboratory blood/urine testing will be performed. Individuals meeting entry criteria will then undergo a one-time series of metabolic studies that will characterize body composition, energy expenditure, glucose tolerance, in-vivo insulin sensitivity, in-vivo glucose metabolism, insulin secretion, and lipid metabolism. Admission should not exceed 5 to 7 days. These studies include an oral glucose tolerance test, 24 hour urine, V02Max study, indirect calorimetry, room calorimetry, DEXA scan, NMR spectroscopy of the leg, percutaneous biopsies of thigh muscle, lower abdominal wall fat biopsies, intravenous glucose tolerance test or hyperinsulinemic euglycemic insulin clamp study.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 胰岛素抵抗综合症为2型糖尿病和心血管疾病的发展提供了“共同土壤”。它是造成我们社会广泛发病和死亡的原因。长期目标是必须找到环境和遗传决定因素以及胰岛素抵抗的生化或分子基础。这些知识将为药物开发提供新的目标，并为预防策略创造合理的方法。在 NIDDM 中，胰岛素抵抗主要是由于骨骼肌中葡萄糖转运系统的刺激受损所致；然而，其分子机制尚未阐明。胰岛素通过细胞内 GLUT4 葡萄糖转运蛋白易位至细胞表面来刺激葡萄糖转运。 NIDDM 中的胰岛素抵抗是由脂肪中 GLUT4 的严重消耗引起的，而肌肉中 GLUT4 表达正常，表明 GLUT4 易位到质膜可能有缺陷。具体目的是检验胰岛素抵抗是由于 GLUT4 运输缺陷导致的假设，该缺陷会损害骨骼肌中胰岛素介导的 GLUT4 易位。为了实现这一目标，将胰岛素敏感抵抗连续体中的健康个体以及 2 型糖尿病患者纳入其中非常重要。同意的受试者将被送往住院 GCRC，在那里将进行全面的病史、体格检查、心电图、活动前/后血压测量以及实验室血液/尿液检测。符合准入标准的个人将接受一系列一次性代谢研究，这些研究将表征身体成分、能量消耗、葡萄糖耐量、体内胰岛素敏感性、体内葡萄糖代谢、胰岛素分泌和脂质代谢。入住时间不应超过5至7天。这些研究包括口服葡萄糖耐量试验、24 小时尿液、V02Max 研究、间接量热法、室内量热法、DEXA 扫描、腿部 NMR 波谱、大腿肌肉经皮活检、下腹壁脂肪活检、静脉葡萄糖耐量试验或高胰岛素正常血糖胰岛素钳夹研究。