Novel PET Imaging of Glucose Transport

葡萄糖转运的新型 PET 成像

• 批准号: 7884582
• 负责人: FARAMARZ ISMAIL-BEIGI
• 金额: $ 37.3万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884582
• 关键词: 2-Fluoro-2-deoxyglucose; 6-deoxyglucose; Animal Model; Animals; Applications Grants; Biochemical; Biodistribution; Biological Assay; Blood; Blood Vessels; Brain; Carbon; Cell Culture Techniques; Clinical; Cyclotrons; Data; Data Collection; Deoxyglucose; Development; Diabetes Mellitus; Discrimination; Disease; Disease Progression; Dose; Energy-Generating Resources; Epidemic; Excretory function; Experimental Models; Eye; Future; GLUT4 gene; Glucose; Glucose Transporter; Goals; Gold; Half-Life; Heart; Hexokinase 2; Human; Hydroxyl Radical; Hyperglycemia; Image; In Vitro; Individual; Injection of therapeutic agent; Insulin; Insulin Resistance; Kidney; Kinetics; Label; Lead; Maintenance; Malignant Neoplasms; Mammalian Cell; Measurement; Measures; Metabolism; Methodology; Methods; Modeling; Monitor; Myocardium; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Obesity; Organ; Patients; Pharmaceutical Preparations; Phosphorylation; Physiological; Positron-Emission Tomography; Protocols documentation; Radiation; Radioactive; Radioactivity; Radiolabeled; Radiopharmaceuticals; Rattus; Research; Running; SLC2A1 gene; Safety; Series; Site; Skeletal Muscle; Spectrum Analysis; Streptozocin; Testing; Time; Tissue Sample; Tissues; Tracer; United States; Urine; Validation; base; bone; diabetic; dosage; glucose analog; glucose metabolism; glucose transport; hexokinase; in vivo; insight; interstitial; mathematical model; novel; pre-clinical; public health relevance; radiotracer; response; skeletal; sugar; uptake; urinary

DESCRIPTION (provided by applicant): Diabetes mellitus is an epidemic in the United States and the world. Type 2 diabetes, the most prevalent form of diabetes, is commonly associated with insulin resistance that often precedes the onset of overt hyperglycemia. Here we propose to further develop and employ a PET-scanning-based methodology to measure glucose transport in skeletal muscle, heart and other tissues under normal and insulin-resistant states. The method has two components: a radiopharmaceutical and a mathematical model. Specifically, we have developed a new radiopharmaceutical 18F-labeled 6-fluoro-6-deoxy-D-glucose ([18F]6FDG) so that the bio- and kinetic distribution of the compound can be quantitatively measured with positron emission tomography (PET). [18F]6FDG, unlike 2-fluoro-2-deoxy-D-glucose ([18F]2FDG) that is commonly used in PET studies, lacks a hydroxyl on carbon 6, and hence is transported but not phosphorylated. The new model relates the PET-measured time-course of radioactive glucose analogs, [18F]6FDG and [18F]2FDG, to the fluxes, transport capacities, phosphorylation and concentrations of glucose. Our overall objective is to validate and apply methodologies for the in vivo quantification of glucose transport, phosphorylation and interstitial and intracellular concentrations in skeletal muscle, heart and brain in normal and abnormal conditions. We use biochemical analyses, in vitro transporter assays, in vivo animal models, PET scanning and mathematical models. We will also perform preclinical and clinical PET studies. Importantly, the PET scan data will enable us to calculate the effect of insulin and other agents on the rate of glucose transport in the above tissues in normal and disease states. The goal is to establish a method that can be used in vivo in humans to determine influx and efflux rates of glucose, intracellular and interstitial concentrations of glucose, the phosphorylation rate of glucose, and most importantly, the maximal glucose transport capacity (Vmax) from the time-series of PET images following sequential injections of [18F]6FDG and [18F]2FDG. Determination of insulin-stimulated glucose transport will provide insight into mechanisms underlying abnormal glucose metabolism in diabetes and will enable monitoring the progression of the disease and its response to specific treatments. Hence, progress on this grant proposal will significantly contribute to ou ability to evaluate and optimally manage patients at the individual level. PUBLIC HEALTH RELEVANCE: The goal of this project is to establish a method for measuring glucose (sugar) transport and metabolism that can be safely used in humans. It will provide insights into abnormal glucose metabolism in diabetes that could lead to better maintenance of the level of glucose in the blood thereby reducing damage to kidneys, eyes, nerves and blood vessels.

描述（由申请人提供）：糖尿病在美国和世界范围内是一种流行病。 2 型糖尿病是最常见的糖尿病形式，通常与胰岛素抵抗相关，胰岛素抵抗通常先于明显的高血糖发生。在这里，我们建议进一步开发和采用基于 PET 扫描的方法来测量正常和胰岛素抵抗状态下骨骼肌、心脏和其他组织中的葡萄糖转运。该方法有两个组成部分：放射性药物和数学模型。具体来说，我们开发了一种新的放射性药物 18F 标记的 6-氟-6-脱氧-D-葡萄糖 ([18F]6FDG)，以便可以通过正电子发射断层扫描 (PET) 定量测量该化合物的生物和动力学分布。与 PET 研究中常用的 2-氟-2-脱氧-D-葡萄糖 ([18F]2FDG) 不同，[18F]6FDG 在碳 6 上缺乏羟基，因此可以被运输但不会被磷酸化。新模型将 PET 测量的放射性葡萄糖类似物 [18F]6FDG 和 [18F]2FDG 的时间进程与葡萄糖的通量、转运能力、磷酸化和浓度联系起来。我们的总体目标是验证和应用正常和异常条件下骨骼肌、心脏和大脑中葡萄糖转运、磷酸化以及间质和细胞内浓度的体内定量方法。我们使用生化分析、体外转运蛋白测定、体内动物模型、PET 扫描和数学模型。我们还将进行临床前和临床 PET 研究。重要的是，PET 扫描数据将使我们能够计算胰岛素和其他药物对正常和疾病状态下上述组织中葡萄糖转运速率的影响。目标是建立一种可用于人体体内的方法，确定葡萄糖的流入和流出速率、细胞内和间质的葡萄糖浓度、葡萄糖的磷酸化率，以及最重要的最大葡萄糖转运能力 (Vmax)顺序注射[18F]6FDG和[18F]2FDG后PET图像的时间序列。确定胰岛素刺激的葡萄糖转运将有助于深入了解糖尿病中葡萄糖代谢异常的机制，并将能够监测疾病的进展及其对特定治疗的反应。因此，这项拨款提案的进展将极大地提高我们在个人层面评估和优化患者管理的能力。公共健康相关性：该项目的目标是建立一种可安全用于人类的测量葡萄糖（糖）转运和代谢的方法。它将深入了解糖尿病中的葡萄糖代谢异常，从而更好地维持血液中的葡萄糖水平，从而减少对肾脏、眼睛、神经和血管的损害。