We previously showed that pituitary adenylate cyclase-activating polypeptide (PACAP) potently stimulates insulin secretion in vivo in mice without altering glucose disposal. Such a combination of results would be explained if epinephrine released by PACAP counteracts the action of insulin and, therefore, that the glucose disposal after PACAP administration is altered by adrenalectomy. In the study reported in this paper, we examined the influence of PACAP27 (1.3 nmol/kg i.v.) on insulin secretion and glucose disposal during an intravenous glucose (1 g/kg) tolerance test in mice subjected to bilateral adrenalectomy 48 h prior to the tolerance test. We found that in control mice, PACAP potentiated glucose-stimulated insulin secretion threefold without affecting glucose disposal. Adrenalectomy potentiated the augmentation by PACAP27 of glucose-stimulated insulin secretion, and in adrenalectomized mice, PACAP27 simultaneously augmented glucose disposal (elimination rate 2.30 +/- 0.07%/min vs. 2.56 +/- 0.05%/min; p = 0.011). Furthermore, PACAP27 augmented glucose elimination stimulated by i.v. insulin administration only in adrenalectomized, but not in control mice. We, therefore, conclude that under in vivo conditions, epinephrine released by PACAP from the adrenals prevents the marked insulinotropic action of the peptide from augmenting glucose disposal.