Clarification of the mechanisms of insulin secretion provides a basis for better understanding and treatment of diabetes. Exocytosis of insulin granules is the final step of the secretory process of insulin secretion. Glucose-induced insulin secretion (GIIS) is the most important mechanism of insulin secretion. GIIS occurs in a biphasic manner: a rapid, sharp phase (first phase), followed by a slow, sustained phase (second phase). According to an existing model, the first phase of insulin secretion results from a readily releasable (RRP) pool comprising docked granules, the second phase from a reserve pool (RP) comprising granules located a distant way from the plasma membrane. However, in contrast the existing model, we have found that both phases in GIIS are caused mainly by restless newcomer (the granules that au fused immediately without docking). In addition to GIIS, potentiation of GIIS is critical for normal regulation of insulin secretion. It is now known that incretin/cAMP signaling potentiates insulin granule exoxytosis by protein kinase A (PKA)-independent as well as PKA-dependent mechanisms, the former involving Epac2 (also referred to as cAMP-GEFII), a guanine-nucleotide-exchange factor (GEF) for Rap1. Epac2/Rap1 signaling potentiates insulin granule exocytosis probably by increasing the size of RRP. We have also found that Epac2 also is a direct target of sulfonylureas (SUs). We previously reported that Epac2 binds to Rim2 (Rab3-interacting molecule 2, now renamed Rim2α. We have studied Rim2α null mice and Rim2α-deficient clonal pancreatic β-cells, to clarify the role of Rim2α in insulin granule exocytosis. We have found that although interaction of Rim2α and Rab3 is required for docking, it is unnecessary for glucose-induced insulin granule exocytosis. This is consistent with the finding that glucose-induced insulin granule exocytosis is caused by the granules that are newly recruited by stimulation and immediately fused to the plasma membrane without docking (restless newcomer above). We have also found that Rim2α interacts with Munc13-1 at basal state and that Munc13-1 dissociates from this Rim2α/Munc13-1 complex by glucose stimulation to activate Syntaxin1, which can form a SNARE complex with SNAP-25 and VAMP-2, which is essential for fusion of insulin granules to the plasma membrane, indicating that Rim2α primes insulin granules for exocytosis. Thus, Rim2α plays a critical role in determining docking and priming states in insulin granule exocytosis. In this symposium, control of insulin granule exocytosis will be discussed, based on our studies.