Beta cell gaba secretion: route, physiological function, and potential for pharmacological modulation in diabetes therapy
According to the World Health Organisation, diabetes affects 422 million people worldwide, over 8% of the entire adult population. The progression of both type 1 and type 2 diabetes is characterised by a decrease in the number and function of beta-cells within pancreatic islets. It has recently been demonstrated that the neurotransmitter γ-aminobutyric acid (GABA), which is produced and secreted from beta cells, is able to slow and even reverse this loss of beta cell capacity. This finding has caused great excitement as treatments which directly address beta cell degeneration would revolutionise diabetes therapy. In order to realise this potential, it is essential that we understand the biogenesis, storage, and secretion of GABA in addition to its functional effects upon islet cells. I therefore propose to characterise a suggested route of GABA secretion from beta cells, assess its role in signalling between islet cells, and identify pharmacological modulators of GABA secretion. This study will be hosted by Patrik Rorsman (University of Gothenburg) with a secondment to AstraZeneca (Mölndal). This interdisciplinary study will combine my experience of applying cutting edge proteomics and genetic editing techniques to the study of protein trafficking with my host's world-leading expertise in islet cell physiology. Successful completion of the proposed work program will reveal fundamental details of islet GABA signalling and likely identify new therapeutic targets for the treatment of diabetes. Furthermore, during a cross-sectorial secondment to AstraZeneca I will carry out a high-throughput phenotypic screen to directly identify small molecule modulators of beta cell GABA secretion.