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

GLP-1 受体运输在胰腺 β 细胞中的作用和调节

• 批准号: MR/M012646/1
• 负责人: Alejandra Tomas
• 金额: $ 49.4万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM012646%2F1
• 关键词: Role; regulation; GLP; receptor; trafficking

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.

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以及与心血管疾病和癌症等不良后果的相关性。 2 型糖尿病患者经常会出现胰腺 β 细胞衰竭，导致胰岛素产生和分泌减少。胰高血糖素样肽-1受体（GLP-1R）激动剂是一类治疗2型糖尿病的新型药物，可激活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细胞总数并诱导食欲下降，从而导致体重增加 GLP-1R 属于 G 蛋白偶联受体 (GPCR) 受体家族。这些受体存在于许多不同类型的细胞中，通常位于细胞的质膜上，它们可以检测来自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定位到细胞中的不同细胞器，这种现象被称为运输，它们被分类为要么被降解，从而终止信号，要么被回收以进行另一轮激活，要么被发送到可以从细胞内部发出信号的特定位置。因此，受体转运具有控制 GLP-1R 活性的潜力，但胰腺 β 细胞中 GLP-1R 的转运尚未得到深入研究。因此，我建议使用最先进的高分辨率显微镜技术研究 GLP-1R 在胰腺 β 细胞中的运输。我将通过操纵细胞中候选蛋白的水平并分析对 GLP-1R 运输的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是否存在贩运缺陷。此外，我将测量受体对细胞中信号的激活，并确定这是否可以通过操纵 GLP-1R 运输来改变。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 β 细胞反应的任何差异。最后，我将评估许多 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疗法，并且已知它们在胰腺 β 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，以及它们如何影响受体产生的信号类型。他们还将确定转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途径，这些方法也可能用于治疗肥胖。

项目成果

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.

• DOI: 10.3390/ijms21218404
• 发表时间: 2020-11-09
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Fang Z;Chen S;Manchanda Y;Bitsi S;Pickford P;David A;Shchepinova MM;Corrêa IR Jr;Hodson DJ;Broichhagen J;Tate EW;Reimann F;Salem V;Rutter GA;Tan T;Bloom SR;Tomas A;Jones B
• 通讯作者: Jones B