Objective: Arginine (L-Arg) has been described as a potentiator of insulin release in the presence of high glucose. However its mode of action on beta-cell activation is not yet clear. On one hand, it has been suggested that beta-cells get activated by electrogenic activity of cationic transporters, which depolarizes the plasma membrane and increases insulin release. Alternatively, it has been suggested that insulin release is caused by L-Arg-derived nitrogen oxides. Method: We used mouse pancreatic tissue slices and whole-cell patch-clamp to measure plasma membrane current and voltage in beta-cells with preserved tissue integrity and cell-to-cell communications. Results: In our experiments we found evidence for both previously suggested pathways. Our results show that L-Arg under same experimental conditions (1mM or 10mM L-Arg in 9-12mM glucose) can elicit differential responses in beta-cells. The beta-cells responded with both hyperpolarization (N=19) decreasing the electrical activity as well as the increase in the frequency of electrical bursts up to continuous bursting (N=32). Conclusion: We conclude that controversies found in the literature regarding the effect of L-Arg on the physiology of beta-cell and insulin release depend on cellular context. Further studies are required to elucidate the detailed mechanism.