title: Direct effects of exendin-(9,39) and GLP-1-(9,36)amide on insulin action, β-cell function, and glucose metabolism in nondiabetic subjects.
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-(3)H]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/min(2) 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.
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Matheni
authors.initials: M
authors.lastname: Sathananthan
authors.forename: Luca P
authors.initials: LP
authors.lastname: Farrugia
authors.forename: John M
authors.initials: JM
authors.lastname: Miles
authors.forename: Francesca
authors.initials: F
authors.lastname: Piccinini
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rizza
authors.forename: Adrian
authors.initials: A
authors.lastname: Vella
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D005260:Female; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; C114437:glucagon-like peptide-1 (9-36)-amide; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005934:Glucagon
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