To assess whether the incretin GLP-1 exerts insulinindependent effects on whole body glucose metabolism, 6,6-02-glucose kinetics were measured in 8 healthy volunteers receiving once GLP-1 (1.2pmol×kg-1 ×min-1), once placebo (0.9% NaCI). Both protocols were performed during hyperglycémie glucose clamping (8 mmol/L) while plasma insulin, glucagon and growth hormone concentrations were maintained constant by triple hormone and somatostatin infusion (pancreatic clamp). After 3 h of GLP-1 infusion glucose rate of disappearance increased to 24.2 ± 2.2nmol×kg-1 ×min-1 compared to 17.212.1 umolxkg-1 xmin-1 during placebo (p < 0.03). Hepatic glucose output decreased during GLP-1 to 25 ±5% of baseline compared to 52 ±6% during placebo (GLP-1 vs placebo: p < 0.01 ). Insulin plasma concentrations were similar in both protocols (NS). However, plasma C-peptide levels increased during GLP-1 to 10 times higher levels than during placebo (p < 0.002). Thus, GLP-1 infusion seems to have insulinindependent glucose-lowering effects by affecting peripheral and hepatic glucose metabolism. The marked increase in plasma C-peptide while plasma insulin levels remained unchanged, suggests an alternative pathway for C-peptide secretion. Swiss National Science Foundation (no 32-39747.93).