Regulation of postprandial (pp) plasma glucose excursions is complex. Insulin and glucagon secretion are thought to play the predominant role. Nevertheless, only 50% of the variation in pp plasma glucose excursions is explained by variations in plasma insulin and glucagon, suggesting that other factors are involved. Theoretically, gastric emptying (GE) should be another important factor. However the impact of GE on pp glucose fluxes has not been studied. Accordingly, we examined the consequences of pramlintide- induced retardation in GE on pp glycemia and glucose fluxes using a combination of a double isotope approach and scintigraphically determined rates of gastric emptying. Fourteen healthy non-diabetic subjects were studied (8 men, 6 women, 40 3 years, bodyweight 78 4 kg, BMI 27.8 1.1kg/m2), 30 µg pramlintide (PRAM) or placebo (PBO) was injected s.c. before subjects ate a mixed meal, scrambled eggs and jello containing 50g glucose, ~25g fat and ~20g protein. At 60 minutes 65±3 vs. 87±2 %, (p<0.001) of initial gastric contents remained in the stomach (PBO vs. PRAM). Thereafter gastric emptying slopes paralleled one another until 240 min. The 50% retention times (T50) were lower when PBO was given (177±9 vs. 227±14 min, p<0.001). GE was greater from 240 min to the end of the experiment in the PRAM experiment, so that only a small but still greater proportion of the meal remained in the stomach at 330 min (5.3±1.8 vs. 11.4±3.0%, p<0.01). Reductions of GE by PRAM markedly reduced pp plasma glucose peak and overall excursions (7.5±0.3 vs. 6.0±0.2 mmol/l, p<0.001 and 5.6±0.1 vs. 5.2±0.1 mmol/l, p<0.001, PBO vs. PRAM respectively) even though peak and overall plasma insulin concentrations were both lower with PRAM (346±37 vs. 211±42 pmol/ml, p<0.01, and 164±13 vs.138±13 pmol/ml, p<0.01). No differences in pp plasma glucagon concentrations were found (66 5 vs. 59 5 pg/ml, ns). The reduction in total glucose appearance in plasma (13.1±0.6 vs. 11.0±0.5 ±mol*kg-1*min-1, p<0.001) was solely attributable to reduction in meal-derived glucose appearance (10.2±0.5 vs. 7.0±0.4 µmol*kg-1*min-1, p<0.001) since endogenous glucose appearance was greater with PRAM (2.9±0.2 vs. 4.0±0.2 µmol*kg^-1*min^-1, p<0.001). Splanchnic glucose uptake was greater with PRAM (26.5±1.6 vs. 32.5±2.1%, p=0.014). Taken together, these data support the concept that GE is an important physiological regulator of pp plasma glucose excursions and glucose fluxes in healthy humans.