Aims: Exenatide is a long acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric emptying effects but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric- independent effect to reduce glycemia, similar to GLP-1. Methods: First, we administered mixed meals to dogs, either with or without exenatide (20 ug, s.c.). Second, to determine whether exenatide-induced lower glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, with exenatide and intraportal exendin 9-39, or with saline. Results: exenatide markedly decreased postprandial glucose (saline: netAUC_0-135 min +526±315 mg/dl•min vs. exenatide: -536±197 mg/dl•min, p=0.03). Importantly, the lowering of plasma glucose occurred without a corresponding postprandial insulin increase but was accompanied by glucagon supression and delayed gastric emptying. Intraportal glucose infusion with exenatide significantly reduced glycemia (97±3 mg/dl vs. 92±3 mg/dl, p<0.001), without hyperinsulinemia or glucagon supression. The exenatide effect to lower glycemia was partly reversed by intraportal exendin 9-39 (95±3 mg/dl exenatide plus antagonist vs. 92±3 mg/dl exenatide; p<0.01). Conclusion: Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.