title: Comparison of the glucose dependency of glucagon-like peptide-1 (7-37) and glyburide in vitro and in vivo.
abstract: The purpose of the present study was to compare the glucose dependency of the insulin secretagogue activity of the sulfonylurea, glyburide, versus that of glucagon-like peptide-1(7-37) [GLP-1(7-37)] in vitro and in vivo. In freshly isolated rat islets, maximally effective concentrations of glyburide (10 micromol/L) and GLP-1(7-37) (10 nmol/L) were equally effective in stimulating insulin secretion in the presence of 15 mmol/L glucose (2.4-fold increase relative to 15 nmol/L glucose alone). At 5 nmol/L glucose, both agents increased insulin secretion, but the effect for glyburide was threefold greater than for GLP-1(7-37) (122% and 41% increase in insulin secretion, respectively). In conscious catheterized rats infused with glucose at a variable rate to clamp plasma glucose concentration at 11 mmol/L, glyburide (1 mg/kg orally) and GLP -1(7-37) (infused intravenously [IV] at 5 pmol/min/kg) produced similar increase in insulin levels (1.8-fold relative to the respective vehicle controls) that were sustained through 60 minutes of measurement. These doses of GLP-1(7-37) and glyburide were then administered to fasted and fed rats (basal plasma glucose concentration, 5.8 and 7.3 mmol/L, respectively). Relative to the vehicle control group, GLP-1(7-37) infusion produced a transitory increase (30%) in plasma insulin concentration and a modest sustained decrease (10% to 20%) in glucose in both fasted and fed rats, whereas glyburide induced a sustained 2.4- and 1.7-fold increase in plasma insulin concentration in fasted and fed rats, respectively, and a 50% decrease in plasma glucose in both fasted and fed rats. Results of these studies demonstrate the higher glucose threshold for the insulin secretagogue activity of GLP-1(7-37) relative to glyburide in vitro and in vivo.
authors.affiliation: Department of Metabolic Diseases, Pfizer Central Research, Groton, CT 06340, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: N A
authors.initials: NA
authors.lastname: Nardone
authors.forename: L M
authors.initials: LM
authors.lastname: Persson
authors.forename: K M
authors.initials: KM
authors.lastname: Andrews
authors.forename: K L
authors.initials: KL
authors.lastname: Shepherd
authors.forename: R W
authors.initials: RW
authors.lastname: Stevenson
authors.forename: J C
authors.initials: JC
authors.lastname: Parker
mesh_terms: D000818:Animals; D005215:Fasting; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects; D008297:Male; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose; C051322:glucagon-like peptide 1 (7-37); D005905:Glyburide