Leucine, like glucose, requires the presence of extracellular calcium in order to stimulate insulin release. Glucose, mannose, leucine and arginine, but neither galactose nor mannoheptulose, stimulate calcium uptake and insulin secretion by isolated islets of Langerhans. Leucine-induced calcium uptake and insulin secretion are inhibited by epinephrine or diazoxide, and unaffected by mannoheptulose. Deuterium oxide, which stabilizes the beta cell's microtubules, inhibits leucine-induced insulin release. These data suggest that the insulinotropic effect of certain sugars and amino acids could be due to a net calcium uptake by the beta cell resulting in the activation of the microtubular-microfilamentous system. 1 This work was supported in part by grants from the Fonds National de la Recherche Scientifique and Fonds de la Recherche Scientifique Medicale (Brussels, Belgium), a grant-in-aid from Farbwerke Hoechst A.G. (Frankfurt, Germany), and the association contract Euratom-Universities of Pisa and Brussels (026-63-04 BIAC).