Agouti-related protein (AgRP) is an orexigenic peptide which is composed of three parts; the amino (N)-terminus, the middle part, and the carboxyl (C)-terminus. AgRP has been implicated in various cell signaling, but the precise role of each parts are currently unclear. In this study, we have attempted to determine which part of AgRP was critical for insulin secretion. We have found that the C-terminus of AgRP specifically increases the intracellular calcium concentration in pancreatic beta Rin5mf cells in a PLC-dependent manner, whereas the middle part and C-terminus have little effects on calcium release. This calcium response can be observed in the freshly isolated primary beta cells also. Moreover, amperometric measurement reveals that the C-terminus of AgRP increases the rate of exocytosis in Rin5mf cells. We further show that this region of AgRP is responsible for insulin secretion in a PLC-dependent manner. Taken together, these results indicate that the C-terminus of AgRP can participate in the insulin secretion in pancreatic beta cells, through the modulation of calcium release.