Epac2-dependent rap1 activation and the control of islet insulin secretion by glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) binds its Class II G protein-coupled receptor to stimulate cyclic adenosine monophosphate (cAMP) production and to potentiate the glucose metabolism-dependent secretion of insulin from pancreatic β cells located within the islets of Langerhans. Prior clinical studies demonstrate that this cAMP-mediated action of GLP-1 to potentiate glucose-stimulated insulin secretion (GSIS) is of major therapeutic importance when evaluating the abilities of GLP-1 receptor (GLP-1R) agonists to lower levels of blood glucose in type 2 diabetic subjects. Surprisingly, recent in vitro studies of human or rodent islets of Langerhans provide evidence for the existence of a noncanonical mechanism of β cell cAMP signal transduction, one that may explain how GLP-1R agonists potentiate GSIS. What these studies demonstrate is that a cAMP-regulated guanine nucleotide exchange factor designated as Epac2 couples β cell cAMP production to the protein kinase A-independent stimulation of insulin exocytosis. Provided here is an overview of the Epac2 signal transduction system in β cells, with special emphasis on Rap1, a Ras-related GTPase that is an established target of Epac2.