Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on Insulin Action, β-Cell Function, and Glucose Metabolism in Nondiabetic Subjects
- Matheni Sathananthan1,
- Luca P. Farrugia1,
- John M. Miles1,
- Francesca Piccinini2,
- Chiara Dalla Man2,
- Alan R. Zinsmeister3,
- Claudio Cobelli2,
- Robert A. Rizza1 and
- Adrian Vella1⇑
- 1Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
- 2Department of Information Engineering, University of Padua, Padua, Italy
- 3Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
- Corresponding author: Adrian Vella, .
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, GLP-1-(9,36)amide, or exendin-(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 μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 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 among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0140/-/DC1.
- Received January 25, 2013.
- Accepted March 25, 2013.
- © 2013 by the American Diabetes Association.
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