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 μmol/L) and GLP-1(7–37) (10 μmol/L) were equally effective in stimulating insulin secretion in the presence of 15 mmol/L glucose (2,4-fold increase relative to 15 mmol/L glucose alone). At 5 mmol/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 increases 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.