It is generally accepted that somatostatin receptor subtype 5 (SSTR5) mediates the inhibition of insulin release. This is due to the fact that in the human, rat, and mouse somatostatin (SST) inhibits insulin release via SSTR5; however, in a preliminary study from Dr. Hsu's laboratory with HIT-T15 [beta]-cells that are derived from hamster insulinoma, it was found that a SSTR2 agonist, but not other SSTR agonists, inhibited insulin release. Since SSTR2 is highly expressed in tumor cells, it is possible that the results from HIT-T15 cells may be due to the nature of tumor cells. Thus, it is hypothesized that in hamsters, SSTR2 mediates somatostatin-induced inhibition of insulin release. Isolated hamster pancreatic islets were used in the present study to test this hypothesis. Both somatostatin (1-100 nM) and nonpeptide SSTR2 agonist L-779,976 (0.1-100 nM) inhibited insulin release in a dose-dependent manner. Nonpeptide agonists for SSTR1, 3, 4, and 5 at the highest concentration studied (1[mu]M) failed to inhibit insulin release. PRL-2903, a peptide SSTR2 antagonist (0.3-1[mu]M), antagonized somatostatin-induced inhibition of insulin release in a dose-dependent manner. It is concluded that in hamster [beta]-cells, somatostatin inhibits insulin release via SSTR2 but not SSTR5.