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Exendin-(9,39) is a competitive antagonist of Glucagon-Like Peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that Exendin-(9,39) and GLP-1-(9,36) amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-3 H]-glucose was infused to mimic the systemic appearance of glucose after a meal. Saline (S), GLP-1-(9,36) amide (G), or Exendin-(9,39) at 30pmol/kg/min (Ex30) or 300pmol/kg/min (Ex300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by Exendin-(9,39) (365±43 vs. 383±35 vs. 492±49 vs. 337±50 mmol per 6hr, S, Ex30, Ex300 and G respectively, p=0.05). Insulin secretion did not differ amongst groups. However, insulin action was lowered by Exendin-(9,39) (25±4 vs. 20±4 vs. 18±3 vs. 21±4 10-4 dl/kg(min per µU/ml), p=0.02), resulting in a lower disposition index during Exendin-(9,39) infusion (1118±118 vs. 816±83 vs. 725±127 vs. 955±166 10-14 dl/kg/mi