The effects of glucose and glucagon on the release of amylin from the isolated perfused rat pancreas were studied. Amylin is a 37-amino acid peptide isolated from pancreatic islet amyloid of patients with non-insulin-dependent diabetes mellitus (NIDDM). Glucose dose-dependently stimulated a biphasic release of amylin from the pancreas in parallel with that of insulin. However, the release of amylin induced by high concentrations of glucose was partially dissociated from that of insulin. The amylin-insulin molar ratios induced by 22.2 mM and 33.3 mM glucose (1.11 +/- 0.05%, 1.05 +/- 0.04%, respectively) were significantly higher than that induced by 16.7 mM glucose (0.90 +/- 0.04%, P less than 0.01 vs 22.2 mM glucose, P less than 0.05 vs 33.3 mM glucose). In the presence of 5.6 mM glucose, glucagon also stimulated the release of amylin from the perfused pancreas in parallel with that of insulin. These findings suggest that amylin may be a secretory protein from the pancreas and that the concomitant secretion of amylin and insulin might contribute to glucose homeostasis.