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

Abstract

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.