Somatostatin (SST) is a major inhibitory hormone that is capable of attenuating both glucagon and insulin secretion from alpha (α) and beta (β) cells respectively within the pancreatic islet of Langerhans. However, there is a critical gap in our understanding of the basic signaling mechanisms downstream of Somatostatin Receptor (SSTR) activation, and how these favor the inhibition of insulin secretion under some circumstances and the inhibition of glucagon secretion under others. Through transcriptomic analysis of purified α and β cell populations I have identified key differences and potential similarities between both which may begin to explain their cell specific SST response. Central to these observations, the SSTR profile which provides the input signal between either cell type is fundamentally different between α and β cells, with both cell types expressing SSTR3 on primary cilia, while α cells additionally express SSTR2 on their cell surface. Somatostatin signaling is typically suggested to lead to the inhibition of calcium and/or cAMP in the islet, but the relative importance of SST’s effect on these parallel signaling cascades is not understood. Furthermore, I have identified a novel SSTR mediated effector mechanism that actively drives the remodeling of filamentous actin (F-actin) with implications for secretory granule exocytosis. As such, my central hypothesis is that selective activation of SSTR3 on β cells and SSTR2 or SSTR3 on α cells will attenuate insulin and glucagon secretion via distinct effects on the quality and kinetics of Ca2+ and cAMP responses and downstream F-actin polymerization. I will pursue this hypothesis through two separate aims anchored by high throughput functional imaging of intact islets. First, I will leverage transgenic mouse lines in which fluorescent reporters of secondary messengers will be delivered to strictly α or β cells. These islets will then be subjected to individual SSTR agonists and antagonists to understand the individual contributions of identified cell specific SSTRs. Second, fluorescent reporters of F-actin dynamics will be employed in live imaging experiments to functionally determine the contribution of SSTR activation on F-actin polymerization and remodeling. These results will be coupled next generation sequencing data of purified populations of α and β cells treated with SST and SSTR type specific antagonists. The results of this aim will characterize an underlying F-actin response to SST contributing to overall hormone attenuation. These approaches are innovative as they leverage the power of high throughput functional imaging of large populations of cells to characterize both a novel mechanism and cell type specific response in high resolution. Collectively, the results of these aims are significant as they will result in a more complete understanding of the mechanisms by which SST succeeds in attenuating insulin and glucagon release under different metabolic conditions. This underst...