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 Sathananthan, Luca P Farrugia, John M Miles, Francesca Piccinini, Chiara Dalla Man, Alan R Zinsmeister, Claudio Cobelli, Robert A Rizza, Adrian Vella, Matheni Sathananthan, Luca P Farrugia, John M Miles, Francesca Piccinini, Chiara Dalla Man, Alan R Zinsmeister, Claudio Cobelli, Robert A Rizza, Adrian Vella

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.

Trial registration: ClinicalTrials.gov NCT01218633.

Figures

FIG. 1.
FIG. 1.
Glucose (A), insulin (B), C-peptide (C), and glucagon (D) concentrations during the saline, Ex 30, Ex 300, and GLP-1-(9,36)amide infused at a rate of 1.2 pmol/kg/min (GLP-1-[9,36]) study days.
FIG. 2.
FIG. 2.
Rates of endogenous glucose production (top panel) and glucose disappearance (bottom panel) during the saline, Ex 30, Ex 300, and GLP-1-(9,36)amide infused at a rate of 1.2 pmol/kg/min (GLP-1-[9,36]) study days.
FIG. 3.
FIG. 3.
Insulin action (Si, A), β-cell responsivity (ϕ, C), DIs (B), and fractional extraction of insulin (D) during the saline, Ex 30, Ex 300, and GLP-1-(9,36)amide infused at a rate of 1.2 pmol/kg/min (GLP-1-[9,36]) study days. *P < 0.05.

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