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

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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.