Gastric inhibitory polypeptide (GIP) produced an increase in immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) release from the isolated perfused rat pancreas. The magnitude of both effects was shown to be dependent on the prevailing glucose concentration. GIP stimulated IRG release at glucose concentrations less than 5.5 mM and IRI release at glucose levels greater than 5.5 mM. Arginine"stimulated IRG secretion in the presence of low glucose (2.7 mM) was potentiated by GIP. In contrast, GIP augmented arginine-stimulated insulin release only in the presence of arginine concentrations of (less than 20 mM, producing no further increase over a maximal arginine stimulus. The glucagonotropic effect of GIP in the presence of arginine was found to be suppressed by glucose, with the opposite effect observed with insulin release. It was concluded that the endocrine pancreatic action of GIP depends to a great degree on existing levels of modulating nutrients in the blood.