The mechanism of sulfonylurea stimulation of insulin release.

The mechanisms for sulfonylurea stimulation of insulin release were explored by studying how these compounds interacted with beta-cell-rich pancreatic islets isolated from ob/ob-mice. Although sulfonylureas from the "second generation" were taken up to a greater extent, there was no direct correlation between the binding to the islets and the stimulation of insulin release. Drugs, which are known to augment the hypoglycemic action of the sulfonylureas, displaced these compounds from serum albumin to the islets. Sulfonylurea binding to the beta-cells is supposed to result from a hydrophobic interaction of the drug with the beta-cell surface counteracted by electrostatic repulsion from fixed negative charges at the cell surface. Like glucose, the sulfonylureas stimulate insulin release by promoting the Ca2+ influx into the beta-cells. The enhanced Ca2+ influx cannot be accounted for by Ca2+-ionophoretic activity but is secondary to a depolarisation of the beta-cells by a mechanism which may involve a reaction with thiol groups in the plasma membrane.