Recently five somatostatin receptor subtypes (SSTR) have been cloned, allowing the development of highly specific selective agonists for these SSTR. The present study was undertaken to determine which SSTR is responsible for the inhibitory effect of somatostatin on islet hormone secretion. Single-pass perfusion of four agonists was performed in pancreata obtained from four cadaveric organ donors using a modified Krebs-media with 3.9 mM glucose. Sequential 10-min specific receptor agonist infusions (5 ng/ml) of DC32-87 (SSTR2), DC25-12 (SSTR3), DC32-97 (SSTR3), or DC32-92 (SSTR5) were performed in random order separated by 10-min basal periods. Infusion of SSTR2 agonist into the isolated perfused human pancreas resulted in a significant inhibition of insulin and C-peptide secretion (insulin = -1468 +/- 480 pM, P < 0.05, and C-peptide = -2328 +/- 437 pM, P < 0.05) but not islet amyloid polypeptide or somatostatin. These results suggest that the inhibitory effect of somatostatin on B-cell secretion is mediated through the subtype-2 receptor within the human islet.