The fast component (mode 1) of Ca(2+)-dependent exocytosis in pancreatic beta-cells, unlike that in adrenal chromaffin cells, is regulated by cytosolic ATP in a concentration-dependent manner. This action of ATP is apparent within 3 min and does not require ATP hydrolysis; rather, it requires the production of cAMP by adenylate cyclase. Moreover, the effect of cAMP is ATP dependent, as revealed by the observation that the fast component of exocytosis is facilitated by ATP, even in the presence of a saturating concentration of cAMP (200 micromol/l). Thus, the amplitude of mode-1 exocytosis depends quadratically on the cytosolic ATP concentration and is facilitated by ATP, even in the absence of an increase in the concentration of cAMP. Given that high glucose concentrations increase the cytosolic ATP concentration, glucose-induced insulin secretion likely involves this action of ATP on mode-1 exocytosis, together with its effect on ATP-dependent K(+) channels. In contrast to the fast component of exocytosis, the slow component (mode 2) of this process is independent of cAMP and ATP and can account for the slow component of insulin secretion, which does not require these nucleotides.