Role and regulation of GLP-1 receptor trafficking in pancreatic beta cells

2型糖尿病和肥胖是两个相互关联的主要公共卫生问题，因为它们的流行程度和与心血管疾病和癌症等不良后果的关联。2型糖尿病患者经常经历胰腺β细胞衰竭，导致胰岛素的产生和分泌减少。胰高血糖素样肽-1受体（GLP-1R）激动剂是一类用于治疗2型糖尿病的新型药物，它激活GLP-1R，进而刺激胰腺β细胞释放胰岛素，比其他疗法更好地控制血糖水平，同时增加β细胞总数，诱导食欲下降，从而导致体重减轻。GLP-1R属于被称为G蛋白偶联受体（gpcr）的受体家族。这些受体存在于许多不同类型的细胞中，通常定位于细胞的质膜，它们可以检测到细胞外的激动剂形式的信号并被激活，将这些信号发送到细胞内并产生细胞反应。一旦被激活，这些受体就会被重新安置到细胞内不同的细胞器中，这种现象被称为运输，在那里它们被分类，要么被降解，信号被终止，要么被循环用于下一轮激活，要么被送到特定的位置，在那里它们可以从细胞内部发出信号。因此，受体转运有可能控制GLP-1R的活性，但胰β细胞中GLP-1R的转运尚未深入研究。因此，我建议使用最先进的高分辨率显微镜技术研究胰β细胞中GLP-1R的贩运。我将通过操纵细胞中候选蛋白质的水平和分析对GLP-1R运输的任何影响来确定调节这种运输的主要参与者。我还将研究人类疾病小鼠模型中存在的贩运缺陷。此外，我将测量受体在细胞中的信号激活，并确定是否可以通过操纵GLP-1R运输来修改这一点。我还将通过测量细胞存活和增殖水平以及它们分泌的胰岛素量来评估细胞反应的差异。最后，我将评估由一些GLP-1R激动剂引起的运输类型，这些激动剂目前正在开发作为新的糖尿病治疗方法，并且已知它们在胰腺细胞中产生的信号类型存在差异。这些研究将确定能够调节β细胞中GLP-1R运输的基本新机制，以及这些机制如何影响受体产生的信号类型。他们还将确定贩运在调节受体对胰岛素分泌，β细胞存活和增殖的已知影响中的重要性，并可能为开发改进的2型糖尿病治疗方法开辟新的途径，这些方法也可能用于治疗肥胖。

Type 2 diabetes and obesity are two interconnected major public health problems, due to their epidemic proportions and association with adverse consequences such as cardiovascular disease and cancer. Patients with type 2 diabetes often experience pancreatic beta cell failure leading to reduced production and secretion of insulin. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of drugs for the treatment of type 2 diabetes that activate the GLP-1R, which in turn stimulates the release of insulin from beta cells in the pancreas, with better control of blood glucose levels than other therapies, while at the same time increasing the total number of beta cells and inducing a reduction in appetite leading to weight loss.GLP-1R belongs to a family of receptors known as G protein-coupled receptors (GPCRs). These receptors exist in many different types of cells, and are normally localised at the plasma membrane of cells were they can detect signals in the form of agonists from outside the cell and get activated, sending these signals inside the cell and generating a cellular response. Once activated, these receptors are relocated to different organelles in the cell in a phenomenon called trafficking, where they are sorted to either be degraded so the signal is terminated, recycled for another round of activation, or sent to specific locations where they can signal from inside the cell. Receptor trafficking has therefore the potential to control the activity of GLP-1R, but the trafficking of GLP-1R in pancreatic beta cells has not been studied in depth. I therefore propose to study the trafficking of GLP-1R in pancreatic beta cells using state-of-the-art high-resolution microscopy techniques. I will identify the main players that regulate this trafficking by manipulating the levels of candidate proteins in the cell and analysing any effects on GLP-1R trafficking. I will also investigate the presence of trafficking defects in mouse models of the human disease. Additionally, I will measure the activation of signals in the cell by the receptor, and I will establish whether this can be modified by the manipulation of GLP-1R trafficking. I will also evaluate any differences in the response of beta cells by measuring cell survival and proliferation levels as well as the amount of insulin they secrete. Finally, I will assess the type of trafficking elicited by a number of GLP-1R agonists which are currently being developed as new diabetes therapies, and which are known to have differences in the type of signals that they generate in pancreatic beta cells.These studies will identify fundamental new mechanisms capable of regulating GLP-1R trafficking in the beta cell, and how these affect the type of signals being generated by the receptor. They will also establish the importance of trafficking in the regulation of the known effects of the receptor on insulin secretion, survival and proliferation of beta cells, and might open new avenues for the development of improved therapy approaches for type 2 diabetes that might also be of use for the treatment of obesity.