The impact of (pancreatic) islet amyloid polypeptide on glucose metabolism and insulin sensitivity was examined in isolated rat livers perfused in a non-recirculating system. Continuous infusion of 10-7mol/1 islet amyloid polypeptide affected neither basal nor glucagon (10-9 mol/1)stimulated glucose output by livers from fed rats, but it did increase the hepatic cyclic AMP release within 44min (7.91_+12.07 vs control: 0.07+0.03pmol-100g body weight-i). The effect of the peptide on the ability of insulin to inhibit glucagon-induced hepatic glycogenolysis was measured in three experimental groups (n = 6). As expected gtucagon (7 x 10 -11 mol/1) increased integral hepatic glucose release within 84 min (763.4_+ 161.7 vs -25.7 + 73.2 gmol. 100 g body weight -1 in the control group, p < 0.001), while insulin (100mU/1) decreased the glucagon-stimulated glucose production (395.2 + 180.0 gmol. 100 g body weight -1, p < 0.01). Simultaneous infusion of 10 -7 mol/1 islet amyloid polypeptide however, was not able to reverse insulin-dependent inhibition of glucagon-stimulated hepatic glucose output (370.0 + 102.5 gmol-100 g body weight -1, NS) or to enhance lactate-induced gluconeogenesis of livers from 24 h fasted rats (n = 8). The glucose production stimulated by 10-~ mol/1 glucagon was slightly greater in islet amyloid polypeptide-pre-treated livers than in a control group without addition of islet amyloid polypeptide (5 rain: 3.60 + 3.36 vs 1.67 + 1.28 gmol-min -1-100 g body weight-i). These results suggest that islet amyloid polypeptide neither directly affects hepatic glycogenolysis nor causes insulin resistance to hormone-sensitive glucose production, but may increase the size of the hepatic glycogen pool by enhancing gluconeogenesis.