These studies assessed the ability of glucose infusions to potentiate the acute insulin response (AIR) to iv isoproterenol (12μg), arginine (750 mg), or glucose (5 g) that was previously inhibited by an infusion of somatostatin (SRIF). SRIF (1.7 μg/min) markedly inhibited the AIR to isoproterenol (AIR before SRIF, 28 ± 1 μU/ml; AIR during SRIF, 8 ± 4 μU/ml; P < 0.025), arginine (AIR before SRIF, 6 ± 2 μU/ml; AIR during SRIF, 1 ± 1 μU/ml; P < 0.01), and glucose (AIR before SRIF, 19 ± 7 μU/ml; AIR during SRIF, 1 ± 1 μU/ml; P < 0.05). The administration of a glucose infusion of 105 mg/min partially restored the AIR to isoproterenol and arginine. Glucose infused at 440 mg/min fully restored the AIR to both isoproterenol (AIR during SRIF plus glucose, 31 ± 4 μU/ml) and arginine (AIR during SRIF plus glucose, 9 ± 2 μU/ml). In contrast, the AIR to glucose was not affected by infusion of glucose (AIR during SRIF plus glucose, 0 ± 1 μU/ml). In the absence of SRIF, glucose infusion potentiates the AIR to isoproterenol and arginine but not to glucose. Therefore, during SRIF infusion, glucose retains the ability to potentiate the AIR to nonglucose stimuli despite the loss of the ability to stimulate insulin release directly. These data suggest that the potentiating effects of glucose and the inhibiting effects of SRIF may be mediated by a common mechanism affecting insulin release.