The role of gastric inhibitory polypeptide (GIP) on insulin secretion in the presence of different glucose concentrations has been studied in perifused microdissected murine islets. Insulin secretion was concentration dependent in the presence of glucose alone: Switching the perifusion buffer from 5.5 to 11.1 and 22.2 mM glucose caused an increase in insulin response assessed as the total integrated area under the curve over a 20-min period (6.4 +/- 0.48 and 12.1 +/- 0.58 ng, respectively; p < 0.01, n = 6). If 11.1 mM glucose perifusion in the presence of GIP was preceded by 5.5 mM glucose alone, the integrated insulin secretion/20 min above basal level was attenuated (1.46 +/- 0.10 vs. 0.37 +/- 0.03 ng; p < 0.01, n = 6), and withdrawal of GIP from the perifusion buffer resulted in the restoration of 11.1 mM glucose-stimulated insulin secretion (1.46 +/- 0.10 vs. 1.98 +/- 0.12 ng). If islets were continuously perifused with 11.1 mM glucose, the addition of GIP did not alter insulin secretion. In contrast, the addition of GIP to 22.2 mM glucose perifusion buffer further enhanced the high glucose-induced insulin secretion above basal (12.1 +/- 0.58 vs. 14.5 +/- 0.84 ng; p < 0.05, n = 6). These observations are consistent with a hypothesis that during a low glucose condition, GIP prevents the risk of hypoglycemia by suppressing insulin secretion, while during a high glucose load, glucose-induced insulin stimulation is potentiated by GIP, presumably to prevent hyperglycemia.