Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro.
This study compares in vitro effects of exendin-4 and glucagon-like peptide (GLP)-1 on basal and glucose-stimulated insulin release from isolated rat islets and in vivo insulinotropic actions of exendin-4 and GLP-1 after an intravenous glucose challenge in rats. In static incubation of isolated islets, changing ambient glucose concentration from 3 mmol/L to 10 mmol/L stimulated insulin secretion 9.8 +/- 1.3-fold. The addition of exendin-4 or GLP-1 (1 nmol/L to 1 micromol/L) increased glucose-stimulated insulin secretion up to 5.8 +/- 1.6-fold and 3.3 +/- 1.0-fold, respectively, over basal rates (defined as no hormones added, 3 mmol/L glucose) and 19.6 +/- 2.3-fold and 15.0 +/- 3.1-fold at 10 mmol/L glucose. In dynamically perfused isolated islets exposed to 7.5 mmol/L glucose, insulin secretion increased 6.4 +/- 1.5-fold, and exendin-4 (20 nmol/L) or GLP-1 (20 nmol/L) increased this similarly by up to 13.5 +/- 2.8 and 12.7 +/- 3.9-fold,respectively. Anesthetized rats administered 5.7 mmol/kg intravenous glucose increased plasma insulin concentration 3.0-fold. Infusion of exendin-4 or GLP-1 increased this to a maximum of 7.6-fold and 5.3-fold, respectively. As with isolated islet studies, in vivo dose responses and concentration responses with exendin-4 and GLP-1 were bell-shaped. When insulinotropic effects were mapped onto the steady-state plasma concentrations associated with these infusion rates, both peptides exhibited bell-shaped concentration responses with peak insulinotropic effects occurring with plasma peptide concentrations of approximately 1 nmol/L in this model. In summary, exendin-4 and GLP-1 exhibited similar insulinotropic potencies (median effective dose [ED(50)]) when assessed on a concentration basis in in vitro and in vivo models, while exendin-4 exhibited greater efficacy (maximum response).
Parkes
D G
DG
Amylin Pharmaceuticals, San Diego, CA 92121, USA.
Pittner
R
R
Jodka
C
C
Smith
P
P
Young
A
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D046508:Culture Techniques; D000077270:Exenatide; D005934:Glucagon / Q000008:administration & dosage / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011498:Protein Precursors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D014688:Venoms
D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide