GIP receptor: The role of post-activation receptor behavior for the incretin effect

肠促胰岛素激素GIP和GLP-1是响应食糜中的营养素而分泌的肠道激素。它们在设定餐后代谢基调中起关键作用。胰腺β细胞是肠促胰岛素的主要靶点。约50%的葡萄糖刺激的胰岛素分泌是肠促胰岛素活性的结果。肠促胰岛素的作用超出β细胞。例如，GIP增强脂肪细胞的胰岛素敏感性，加强这些细胞中的餐后合成代谢。由于肠促胰岛素的“胰岛素原”活性（即，增强胰岛素分泌和作用），它们是治疗胰岛素抵抗的优良药物靶标。一些治疗承诺已经实现，因为目前正在使用靶向肠促胰岛素的药物。肠促胰岛素对全身生理学的影响虽然复杂，但已经有相当详细的描述。我们在细胞水平上对肠促胰岛素生物学的了解仍存在更大的差距，尤其是GIP。本项目的目标是通过对肠促胰岛素受体生物学的彻底检查来解决这些差距。肠促胰岛素通过G蛋白偶联受体（GPCR）发出信号。已经确定的是，GPCR活化后的贩运对其生物效应有很大贡献。我们已经创建了工具来研究脂肪细胞（一种生理相关的细胞类型）中GIP受体（GIPR）的行为。使用这些工具，我们已经：i）确定了GIP效应对培养的脂肪细胞的影响; ii）确定了GIPR运输不符合规范的GPCR行为; iii）确定了GIPR编码变体（Q354 E）的细胞内运输与主要的人GIPR序列相比发生了改变。Q354 E变异与人类代谢改变有关。因此，这些结果提供了异常贩运与GIPR功能之间的联系。在这里，我建议在此基础上进一步定义肠促胰岛素在细胞水平上的生物学，并将这些知识扩展到整个动物研究。我们将：1）表征GIPR运输的调节和GIPR增强脂肪细胞中胰岛素作用的控制。 2)定义β细胞中肠促胰岛素受体（GIPR和GLP-1）的运输，将肠促胰岛素受体细胞生物学与受体的生理活性联系起来。这些研究还将揭示一种肠促胰岛素受体的行为/活性如何影响另一种的行为/活性。3)研究GIPR-Q354变体对小鼠代谢的影响，这些小鼠经工程改造以模拟人GIPR-Q354变体。这些研究将提供独特的见解的生理中断所引起的改变后激活贩运的GIPR。该项目解决了肠促胰岛素生物学知识的重大空白，这将为未来利用肠促胰岛素系统治疗代谢性疾病提供信息。

The incretin hormones, GIP and GLP-1, are gut hormones secreted in response to nutrients in the chyme. They have key roles in setting postprandial metabolic tone. Pancreatic β cells are a principal target of the incretins. About 50% of glucose-stimulated insulin secretion is the result of incretin activity. Incretins have effects beyond β cells. For example, GIP enhances insulin-sensitivity of adipocytes, reinforcing a postprandial anabolic metabolism in those cells. Because of the “pro-insulin” activity of the incretins (i.e., enhanced insulin secretion and action), they are excellent drug targets for the treatment of insulin resistance. Some of that therapeutic promise has already been met, as drugs targeting incretins are currently in use. The effects of incretins on whole body physiology, though complex, are fairly well described. More significant gaps remain in our knowledge of incretin biology at the cellular level, which is especially true for GIP. The objective of this project is to address those gaps by a thorough examination of incretin receptor biology. Incretins signal by G protein-coupled receptors (GPCRs). It is well established that the post-activation trafficking of GPCRs contributes significantly to their biological effects. We have created tools to study the behavior of the GIP receptor (GIPR) in adipocytes, a physiologically relevant cell type. Using those tools, we have: i) defined the effect of GIP effect on cultured adipocytes; ii) established that GIPR trafficking does not conform to canonical GPCR behavior; iii) established that the intracellular trafficking of a GIPR coding variant (Q354E) is altered compared to the predominant human GIPR sequence. The Q354E variant is associated with human metabolic alterations. Therefore, those results provide a link between aberrant trafficking and GIPR function. Here I propose to build on that foundation to further define incretin biology at the cellular level and to extend that knowledge to whole animal studies. We will: 1) Characterize regulation of GIPR trafficking and control of GIPR enhancement of insulin action in adipocytes. 2) Define the trafficking of the incretin receptors (GIPR and GLP-1) in β cells, linking incretin receptor cell biology to physiologic activities of the receptor. These studies will also reveal how the behavior/activity of one incretin receptor influences the behavior/activity of the other. 3) Investigate the impact of the GIPR-Q354 variant on metabolism in studies of mice engineered to model the human GIPR-Q354 variant. These studies will provide unique insights into the physiological disruptions induced by altered post-activation trafficking of the GIPR. This project addresses significant gaps in knowledge of incretin biology, an enhanced understanding that will inform future efforts to harness the incretin system in the treatment of metabolic diseases.