title: Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice.
abstract: The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first- and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED(50) parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of ~1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.
authors.affiliation: Dept. of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, USA.
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Chan
authors.forename: Ritesh
authors.initials: R
authors.lastname: Jain
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacini
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D005947:Glucose / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008954:Models, Biological
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose