Novel PET Imaging of Glucose Transport

摘要 糖尿病在美国和全世界都是一种流行病。2型糖尿病，最常见的 糖尿病的一种形式，通常与胰岛素抵抗有关，通常在明显的糖尿病发作之前 高血糖症。在这里，我们建议进一步开发和使用基于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 各州。该方法由两部分组成：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)，因此 该化合物的生物分布和动力学分布可以用正电子发射定量测量。 断层扫描(PET)。[18F]6FDG与2-氟-2-脱氧-D-葡萄糖([18F]2FDG)不同 PET研究，在碳6上缺乏羟基，因此是运输的，但不是磷酸化的。新的 模型将PET测量的放射性葡萄糖类似物[18F]6FDG和[18F]2FDG的时间过程关联到 通量、转运能力、磷酸化和葡萄糖浓度。 我们的总体目标是验证和应用体内葡萄糖定量的方法学 骨骼肌、心脏和脑的转运、磷酸化及细胞间和细胞内浓度 在正常和不正常的情况下。我们使用生化分析，体外转运蛋白分析，活体 动物模型、正电子发射计算机断层扫描和数学模型。我们还将进行临床前和临床PET检查 学习。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 葡萄糖在正常和疾病状态下在上述组织中的转运速度。 目标是建立一种可以在人体内使用的方法来确定内流和外流速度 葡萄糖、细胞内和间质中的葡萄糖浓度、葡萄糖的磷酸化率，以及 最重要的是，来自PET图像时间序列的最大葡萄糖转运能力(Vmax) 在连续注射[18F]6FDG和[18F]2FDG后。 对胰岛素刺激的葡萄糖转运的测定将为深入了解 糖尿病的糖代谢异常，将使监测疾病的进展和其 对特定治疗的反应。因此，这项赠款提案的进展将大大有助于我们的 在个人层面上评估和优化管理病人的能力。

Abstract 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 our ability to evaluate and optimally manage patients at the individual level.