Novel PET Imaging of Glucose Transport

摘要 糖尿病是一种流行病在美国和世界。2型糖尿病，最普遍的 糖尿病的一种形式，通常与胰岛素抵抗有关，胰岛素抵抗通常发生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采用基于PET扫描的方法， 测量正常和胰岛素抵抗下骨骼肌、心脏和其他组织中的葡萄糖转运 states.该方法有两个组成部分：放射性药物和数学模型。具体地说， 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] 6 FDG）， 该化合物的生物和动力学分布可以用正电子发射定量测量 断层扫描（PET）。[18F] 6 FDG，不像通常用于治疗糖尿病的2-氟-2-脱氧-D-葡萄糖（[18F]2FDG）， PET研究，缺乏碳6上的羟基，因此被转运但不被磷酸化。新 模型将PET测量的放射性葡萄糖类似物[18 F] 6 FDG和[18 F]2FDG的时间过程与 葡萄糖的通量、转运能力、磷酸化和浓度。 我们的总体目标是验证和应用体内葡萄糖定量方法 骨骼肌、心脏和脑中的转运、磷酸化以及间质和细胞内浓度 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 问题研究重要的是，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的速率。 我们的目标是建立一种方法，可以在人体内使用，以确定流入和流出率 葡萄糖的浓度、葡萄糖的细胞内和间质浓度、葡萄糖的磷酸化速率，以及 最重要的是，来自PET图像的时间序列的最大葡萄糖转运能力（Vmax 随后依次注射[18 F] 6 FDG和[18 F]2FDG。 确定胰岛素刺激的葡萄糖转运将提供深入了解的机制， 糖尿病中的异常葡萄糖代谢，并将能够监测疾病的进展及其 对具体治疗的反应。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最佳管理患者的能力。

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.