Insulin-like growth factors I and II (IGF-I and IGF-II) are thought to primarily regulate the growth and development of a number of tissues. However, it has recently been observed that when IGF-I is infused into man and animals, plasma insulin levels fall, raising the possibility that IGF-I may also be an inhibitor of insulin secretion. This study used the in vitro perfused rat pancreas and recombinant human IGF-I and IGF-II to determine if either of these peptides affected insulin and/or glucagon secretion from normal rats. IGF-I given with 7.8 mM glucose suppressed insulin secretion by as much as 65%, with the half-maximal effect occurring at less than 10 ng/ml. Glucose-induced insulin secretion (7.8 mM glucose) and arginine-induced insulin secretion (10 mM arginine plus 7.8 mM glucose) were inhibited equally (40%) by 2 ng/ml IGF-I. Insulin secretion returned to normal within minutes of stopping IGF-I. IGF-II (200 ng/ml) also suppressed insulin release, but the effect was less pronounced than for IGF-I and was present at 16.7 mM glucose, but not at 7.8 mM glucose. In contrast to the effects on insulin release, neither peptide altered glucagon secretion. We conclude from these results that 1) IGF-I at physiological concentrations is a potent inhibitor of both glucose- and arginine-induced insulin secretion; 2) the magnitude of the inhibition depends on the background glucose concentration; and 3) the inhibition fully reverses when IGF-I is stopped. These results support an in vivo effect of IGF-I to modulate insulin output.