Multi-Tracer PET Quantitation of Insulin Action

描述(申请人提供)：2型糖尿病患者的胰岛素抵抗(IR) 糖尿病和肥胖症一样，都以组织特异性的方式表达。至 对IR的发病机制有了新的认识，并为评估治疗，它 拥有组织特异性评估方法将非常有用，这种方法可以 用于人类调查。这项提议的目标是发展和 验证一种新的三重示踪剂正电子发射断层扫描(PET)成像 方法检测体内胰岛素刺激的血流量、葡萄糖转运和 健康人和胰岛素抵抗患者骨骼肌中葡萄糖的磷酸化 个人。我们将使用这种方法来检验控制的假设 胰岛素对骨骼肌糖代谢的促进作用 流动、运输和磷酸化。我们还假设胰岛素抵抗 源于这种分布式控制系统的损害，而不是 从一个占主导地位的狭窄地带。 我们确定了五个具体目标。第一个目标是开发 三重示踪PET方法，将使用15O-H2O来测量血流和 组织灌注，11C-3-O-甲基葡萄糖作为葡萄糖的选择性示踪剂 转运和18F-2-脱氧-2-氟葡萄糖作为葡萄糖的选择性示踪剂 运输和磷酸化。由于分子的半衰期不同， 三个正电子(15O、11C和18F)，这些模拟将在 同一个体的一项新陈代谢研究。我们将使用动态PET成像来 监测组织代谢的时间进程，我们的第二个目标是开发 并测试数学模型以提取定量的生理信息。 我们将使用隔室和非隔室模型，以及参数映射， 并运用统计学原理检验每种方法的适当性。这个 这3种示踪剂的生物化学特异性将为 对这些建模方法进行了测试和优化。第三个目标是使用 研究2型胰岛素抵抗的三重示踪PET方法及模型 糖尿病和肥胖症。第四个目标将是检查 胰岛素刺激组织中的FFA升高(通过输注脂肪实现) 灌流、葡萄糖转运和磷酸化，第五个目标是 检查运动对胰岛素敏感性的增强作用。

DESCRIPTION (provided by applicant): Insulin resistance (IR) in type 2 diabetes mellitus, as well as in obesity, is expressed in a tissue specific manner. To gain new insight into the pathogenesis of IR and for assessing therapy, it would be very useful to have tissue specific methods of assessment that can be used in human investigations. The goal of this proposal is to develop and validate a novel triple-tracer positron emission tomography (PET) imaging method to examine in vivo insulin-stimulated blood flow, glucose transport and glucose phosphorylation in skeletal muscle in healthy and insulin resistant individuals. We will use this method to test the hypothesis that control over insulin stimulated glucose metabolism in skeletal muscle in distributed across flow, transport and phosphorylation. We also posit that insulin resistance derives from an impairment of this system of distributed control rather than from a single dominating constriction. We have identified five specific aims. The first aim that of developing the triple tracer PET method, will be to use 15O-H2O to measure blood flow and tissue perfusion, 11C-3-O-methyl glucose as a selective tracer for glucose transport and 18F-2-deoxy-2-fluoro-glucose as a selective tracer for glucose transport and phosphorylation. Because of the differences in half-life of the three positrons (15O, 11C and 18F), these analogs will be used in series during one metabolic study in the same individual. We will use dynamic PET imaging to monitor the time course of tissue metabolism and our second aim is to develop and test mathematical models to extract quantitative physiological information. We will use compartmental and non-compartmental models, and parametric mapping, and test the appropriateness of each approach by statistical principles. The biochemical specificity of the 3 tracers will provide rigorous criteria for testing and optimizing these modeling methods. The third aim will be to use the triple tracer PET method and modeling to study insulin resistance in type 2 diabetes mellitus and obesity. The fourth aim will be to examine the effects of elevated FFA (achieved by lipid infusion) upon insulin-stimulated tissue perfusion, glucose transport and phosphorylation, and the fifth aim will be to examine enhancement of insulin sensitivity by exercise.