GLP-1 Infusion Research Articles

Comparison of the glucose dependency of glucagon-like peptide-1(7–37) and glyburide in vitro and in vivo

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.

Glucose-dependent action of glucagon-like peptide-1(7-37) in vivo during short- or long-term administration

In vitro, truncated glucagon-like peptides [GLP-1(7-36)-amide and GLP-1(7-37)] increase insulin secretion in a glucose-dependent manner, and desensitization to the action of GLP-1(7-37) has been demonstrated acutely with high concentrations. The purpose of these studies was to evaluate the glucose dependency and threshold of GLP-1(7-37) action in normal rats and in a rat model of type II diabetes and to assess the effects of long-term administration in vivo. All studies were conducted in conscious catheterized rats. An intravenous (IV) infusion of GLP-1(7-37) at 0.5, 5, or 50 pmol/min/kg during the second hour of a 2-hour 11-mmol/L hyperglycemic clamp in Sprague-Dawley rats produced a dose-related enhancement of the glucose-induced increase in plasma insulin concentration. A 1-hour infusion of a submaximal dose of GLP-1(7-37) (5 pmol/min/kg IV) in fasted and fed Sprague-Dawley rats produced small transient increases in plasma insulin (incremental increases above basal, 72 ± 27 and 96 ± 28 pmol/L, respectively) and decreases in plasma glucose (to levels ≥ 5.2 mmol/L). Infusion of GLP-1(7-37) (5 pmol/min/kg IV) during a hyperglycemic clamp at two sequentially increasing concentrations of glucose, 11 and 17 mmol/L, produced incremental increases in insulin of 600 and 1,200 pmol/L, respectively, relative to levels in clamped control rats. Similarly, infusion of GLP-1(7-37) (5 pmol/min/kg IV) in hyperinsulinemic, hyperglycemic Zucker diabetic fatty (ZDF) rats produced a transitory increase in plasma insulin concentration and normalized the plasma glucose concentration. Infusion of GLP-1(7-37) (5 pmol/min/kg IV) for 6 hours in rats maintained at 11 mmol/L glucose resulted in a sustained approximately twofold enhancement of the plasma insulin concentration, suggesting no evidence of acute desensitization. In rats infused with GLP-1(7-37) for 5 days at 15 pmol/min/kg (osmotic minipump subcutaneously), there was a small increase in basal plasma insulin concentration and no effect on glucose. In response to a glucose infusion (to clamp plasma glucose at 11 mmol/L), rats infused with GLP-1(7-37) for 5 days had greater than 50% higher insulin concentrations than vehicle-infused rats. There was no effect of long-term GLP-1(7-37) treatment on food intake or pancreatic insulin content. These results demonstrate the glucose dependency of GLP-1(7-37) in vivo. The incremental insulin response to GLP-1(7-37) was increased with hyperglycemia, and the glucose threshold for GLP-1(7-37) action was approximately 5 mmol/L. These results also demonstrate that GLP-1(7-37) is active after many hours or days of sustained exposure.

Effects of Glucagon-Like Peptide 1 (7-36) Amide and Glucagon on Amylin Release from Perfused Rat Pancreas

The effects of glucagon-like peptide 1 (7-36) amide [GLP-1 (7-36) amide] and glucagon on the release of islet amyloid polypeptide (IAPP), or amylin, from the isolated perfused rat pancreas were studied. In the presence of 5.6 mM glucose, GLP-1 (7-36) amide and glucagon stimulated the release of amylin from the perfused pancreas. The infusion of GLP-1 (7-36) amide at a concentration of 10(-9) M elicited a biphasic release of amylin similar to that of insulin. The cumulative output of amylin induced by 10(-9)M GLP-1 (7-36) amide was significantly higher than that by 10(-9)M glucagon (p less than 0.01). The amylin/insulin molar ratios induced by GLP-1 (7-36) amide and glucagon were about 1% and did not differ significantly. These findings suggest that GLP-1 (7-36) amide and glucagon stimulate the release of amylin from the pancreas and that the concomitant secretion of amylin and insulin might contribute to glucose homeostasis.

Glucagon-like peptide-1 (7–36)-NH2: a physiological inhibitor of gastric acid secretion in man

Glucagon-like peptide (GLP)-1 (7-36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7-36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7-36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7-36)-NH2 as a physiological inhibitor of gastric acid secretion in man.