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 i ntravenous glucose challenge in rats. In static incubation of isolated isle ts, changing ambient glucose concentration from 3 mmol/L to 10 mmol/L stimu lated insulin secretion 9.8 +/- 1.3-fold. The addition of exendin-4 or GLP- 1 (1 nmol/L to 1 mu mol/L) increased glucose-stimulated insulin secretion u p 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 is lets 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 simila rly 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 stud ies, in vivo dose responses and concentration responses with exendin-4 and GLP-1 were bell-shaped. When insulinotropic effects were mapped onto the st eady-state plasma concentrations associated with these infusion rates, both peptides exhibited bell-shaped concentration responses with peak insulinot ropic 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 [ED50]) when assessed on a concentration basis in in vitro and in vivo models, while exendin-4 exhibit ed greater efficacy (maximum response). Copyright (C) 2001 by W.B. Saunders Company.