To investigate the effect of islet amyloid polypeptide (IAPP, amylin) exposure on insulin secretion in vivo, the plasma glucose level of conscious rats was clamped at 11.1 mmol/l (hyperglycemic clamp) during the last 2 h of a 24-h infusion study. Group parameters were A, 24-h saline; B and C, 22-h saline followed by 2-h IAPP (B, 8.5 pmol/min; C, 85 pmol/min), and D, 24-h IAPP (85 pmol/min). Induced hyperglycemia increased plasma insulin concentration by 426 +/- 34 pmol/l in control rats (group A). This effect on plasma insulin was reduced by 31% and 53% during short-term IAPP infusion (group B, 8.5 pmol/min, 294 +/- 41 pmol/l; C, 85 pmol/min, 202 +/- 25 pmol/l; short-term effect, P < 0.0001), whereas insulin levels tended to increase after 24 h of continuous IAPP exposure (group D, 682 +/- 120 pmol/l; P < 0.05 vs. group A). Glucose infusion rate required to maintain constant hyperglycemia fell dose dependently during short-term but not during long-term IAPP infusion (mumol.kg-1.min-1: group A, 203 +/- 11; B, 154 +/- 7; C, 119 +/- 7; D, 212 +/- 9; short-term effect, P < 0.0001). In parallel, muscle glycogen content was dose dependently reduced by short-term IAPP exposure. We conclude that IAPP inhibits glucose-stimulated insulin secretion and decreases muscle glycogen storage in conscious rats in vivo.