Biophysical and Pharmacological Properties of Glucagon-Like Peptide-1 in Rats Under Isoflurane Anesthesia

Abstract

Glucagon-like peptide-1 (GLP-1) increases insulin secretion and has an important role in maintaining glucose homeostasis. In this study, we evaluated the biophysical and pharmacological properties of GLP-1 by performing in vivo and in vitro experiments to determine the applicability of GLP-1 in glycemic control in rats under isoflurane anesthesia. Levels of portal GLP-1, insulin, and glucose and dipeptidyl peptidase-4 activity were measured in the basal fasting state and after gastric glucose load before, during, and after exposure to 30% O(2) in air (control) or 1.4% isoflurane in a mixture of 30% O(2) and air. The direct effects of isoflurane on GLP-1 secretion were assessed in human enteroendocrine NCI-H716 cells. Insulin release from isolated pancreatic islets was measured using a radioimmunoassay. Single pancreatic β-cell membrane potentials were recorded using whole-cell current-clamp patches perforated by β-escin. In fasting rats, inhalation of isoflurane led to a decrease in the basal levels of GLP-1 but did not affect insulin and glucose levels. Levels of GLP-1, insulin, and glucose increased after gastric administration of glucose in control rats. However, isoflurane attenuated the glucose-induced increase in GLP-1 and insulin levels and increased plasma glucose levels. In contrast, isoflurane did not affect dipeptidyl peptidase-4 activity before or after gastric glucose loading. Isoflurane (0.35 mM) inhibited GLP-1 release in NCI-H716 cells; this finding was similar to that observed in in vivo studies. In perifusion experiments, isoflurane (0.35 mM) inhibited glucose-induced insulin release, whereas exogenous GLP-1 (10 nM) enhanced insulin release. Importantly, combined administration of isoflurane and GLP-1 enhanced both phases of glucose-induced insulin release to an extent similar to that achieved with GLP-1 alone. Whole-cell patches showed that exposure to GLP-1 (10 nM) led to nearly complete restoration of glucose-stimulated depolarization that had been suppressed by isoflurane (0.35 mM). GLP-1 secretion is impaired during isoflurane anesthesia. However, our study showed that the insulinotropic action of GLP-1 was not affected by isoflurane. Furthermore, exposure to GLP-1 increased the membrane activity of pancreatic β-cells, preventing isoflurane-induced impairment of glucose-induced insulin secretion. These results support the hypothesis that GLP-1-based therapy may be a useful approach for achieving intraoperative glycemic control.