Pancreastatin is known to be produced in islet B cells and to inhibit insulin secretion. In this study, we examined whether the peptide affects insulin secretion from the perfused rat pancreas during raising or lowering the glucose concentration within the physiological range, We found that synthetic porcine pancreastatin (15 nmol L(-1)) significantly inhibited the first phase (5 min) of insulin release induced by raising the glucose concentration from 4.2 to 8.3 mmol L(-1) (Pi 0.05) without affecting the second phase. Furthermore, the fall in insulin secretion induced by lowering the glucose concentration from 8.3 to 5.5 mmol L(-1) was significantly exaggerated in presence of pancreastatin during the first 5 min (P < 0.05). In contrast. pancreastatin did not affect the inhibition of insulin secretion induced by either the alpha(2)-adrenoceptor agonist. clonidine (2 nmol L(-1)), or the P-1-purinoceptor (A(1)-subtype) agonist. N-6(+) -phenylisopropyladenosine (D) PIA) (1.65 mu mol L(-1)). in conclusion, our results show that pancreastatin is a modulator oi the early changes in insulin secretion alter increase or decrease of the glucose concentration within the physiological range, This suggests that pancreastatin is a modulator of glucose-stimulated insulin secretion.