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

  1. Adrian Vella, MD1
  1. 1Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN
  2. 2Department of Information Engineering, University of Padua, Padua, Italy.
  3. 3Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
  1. Corresponding author: Adrian Vella, Email: vella.adrian{at}mayo.edu

Abstract

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 [3-3H]-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/min2 per pmol/l, p=0.003). Endogenous glucose production and glucose disappearance did not differ significantly amongst groups. We conclude that Exendin-(9,39), but not GLP-1-(9,36) amide, decreases insulin action and disposition index in healthy humans.

  • Received January 25, 2013.
  • Accepted March 25, 2013.

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