Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on Insulin Action, β-Cell Function, and Glucose Metabolism in Nondiabetic Subjects

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 beta-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-H-3]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exenclin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) 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 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among 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 mu U/mL]; P = 0.02), resulting in a lower disposition index (DI) during exenclin-(9,39) infusion (1,118 +/- 118 vs. 816 +/- 83 vs. 725 +/- 127 vs. 955 +/- 166 10(-14) dL/kg/min(2) per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exenclin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans. Diabetes 62:2752-2756, 2013