Extrapancreatic and pancreatic actions of glibenclamide in rats

Summary The aim of this study was to investigate the influence of glibenclamide on insulin release via insulinotropic gut factors and via a direct action on the pancreas. Maximum peripheral IRI levels appeared 1 minute after intragastric administration of the minimal effective dose of glibenclamide to rats. The corresponding drug levels were high (600 ng/g) in the duodenal mucosa, but low (2 ng/ml) in the peripheral serum. These concentrations were too low to cause insulin release by direct action on the pancreas. Intragastric glibenclamide increased the amount of duodenal insulin releasing activity (DIRA) in the mucosa immediately after drug administration. When glibenclamide was dissolved in plasma at a high concentration (1 g/ml) and then injected into the coeliac trunk of an in-situ rat pancreas preparation, no additional effect on portal IRI levels was measured as compared with injection of serum alone. In contrast significant IRI release was noticed when glibenclamide was dissolved in serum (1 g/ml) of rats pretreated with the drug intragastrically. The plasma of pretreated rats without addition of glibenclamide was ineffective. The results suggest that glibenclamide may have two effects, one releasing insulin at the pancreas directly, and the other inducing the release of a gastrointestinal factor which amplifies the first effect. Neither glibenclamide nor the factor alone can provoke an IRI release under physiological conditions. The possible importance of these findings for the regulation of insulin secretion is discussed.Presented at the 11th EASD Congress, Munich, September 1975