We have recently identified a role for the Wnt signalling factor β-catenin in mediating the effect of glucose on insulin secretion from pancreatic β-cells. β-catenin is known to play two major roles 1) as a transcriptional activator in the nucleus together with TCF-7L2 and 2) in regulating the actin cytoskeleton at the cell membrane. Our previous studies have shown that β-catenin is required for glucose stimulated insulin secretion (GSIS) in INS-1E pancreatic β-cells. We have also shown that glucose regulates the phosphorylation of β-catenin at ser552 via a novel mechanism involving cAMP/PKA. N-terminal phosphorylation targets β-catenin for proteosomal degradation however C-terminal phosphorylation, such as at ser552, has not been well characterised but is thought to confer stability. We hypothesise that C-terminal phosphorylation of β-catenin alters its role within the cell from a transcriptional activator to modifying the actin cytoskeleton to allow insulin release. This would provide an explanation as to why glucose, cAMP and increntin hormones increase GSIS from pancreatic β-cells and may explain why TCF-7L2 is a major susceptibility gene for type-2 diabetes. Here we provide further evidence, through the use of Total Internal Reflection Fluorescence microscopy, insulin secretion experiments and confocal microscopy of stained cortical actin, that β-catenin is required for β-cell GSIS and is also important in mediating the effect of increntin hormones, such as GLP-1, on GSIS. Inhibition of β-catenin and reduction of ser552 phosphorylated β-catenin correlated with decreased GSIS and signification redistribution of insulin granules located near the cell membrane. We also have studies underway to create a transgenic mouse model that will specifically investigate the importance of β-catenin ser552 phosphorylation in vivo. Our data thus far show an important role for β-catenin in the regulation of GSIS and provides a potential mechanism by which both phosphorylation and physical interaction with other factors may dramatically alter the role of β-catenin within the cell.