To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol.kg-1 x min-1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of i.v. saline; short-term amylin exposure: 22 h of i.v. saline followed by 2 h of i.v. amylin (20 micrograms/h); long-term amylin exposure: 24 h of iv amylin (20 micrograms/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (mumol.kg-1 x min-1; control group, 106.0 +/- 15.0; short-term i.v. amylin, 62.7 +/- 15.0; p < 0.005). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9 +/- 6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52 +/- 0.15 to 2.09 +/- 0.12 mmol/l; p < 0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10 +/- 0.09 and 2.04 +/- 0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (> 22 h) amylin exposure, being apparently independent of induced hypocalcemia.