This Fellowship combines the expertise of the host group in the expression and function of islet G protein-coupled receptors (GPCRs) with the Fellow’s previous experience in identifying the role of retinoic acid and neurotrophin receptors in islet function. GPCRs are the targets of up to 50% of all prescription drugs and Byetta, a GLP-1 receptor activator used to treat Type 2 diabetes (T2D), provides proof of concept that ligands targeting islet GPCRs may be developed for T2D therapies. However, Byetta has been associated with pancreatitis and kidney dysfunction, so there is a need for novel T2D therapies with minimal side-effects. There are over 50 million people in Europe with T2D, which arises when insulin secretion is unable to compensate for insulin resistance in target tissues. Agents that increase insulin secretion and/or stimulate b-cell proliferation will have beneficial effects in T2D where insulin secretion is compromised through impaired stimulus-secretion coupling and/or reduced b-cell mass. This Fellowship project has two main objectives: Investigating the role of islet short chain fatty acid receptors (FFAR2 and FFAR3) in regulating beta-cell function and identifying novel islet GPCRs that regulate insulin secretion and/or beta-cell mass. The host lab has identified expression of FFAR2/3 by islets and the Fellow will determine whether they have therapeutic potential for the treatment of T2D. In addition, orphan GPCR beta-arrestin reporter cell lines will be used to detect activating ligands secreted by islets and functional effects of those orphan GPCRs will be established following knockdown of their expression. This is an ambitious project that has the potential to provide drug discovery leads for T2D therapies. The Fellow will benefit from training in state of the art islet biology methodologies in an internationally acknowledged environment for diabetes research, which will facilitate his transition into a fully independent research scientist.