Sulfonylurea induced β-cell apoptosis in cultured human islets

Loss of beta-cell mass and function raises a concern regarding the application of sulfonylureas for the treatment of type 2 diabetes because previous studies have shown that agents that cause closure of inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels, such as tolbutamide and glibenclamide, induce apoptosis in beta-cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on beta-cell apoptosis in human islets. Human islets from six organ donors were cultured onto extracellular matrix-coated plates and exposed to glibenclamide, repaglinide, or nateglinide. The doses of the three compounds were chosen according to detected maximal effects, i.e. efficacy. Exposure of human islets for 4 h to 0.1 and 10 muM glibenclamide induced a 2.09- and 2.46-fold increase in beta-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 muM) did not change the number of apoptotic beta-cells. At low concentration ( 10 muM), nateglinide did not induce beta-cell apoptosis. However, at high concentration of 1000 muM, it induced a 1.49-fold increase in the number of apoptotic beta-cells. Prolonged exposure for 4 d of the islets to the secretagogues induced beta-cell apoptosis. The increase was of 3.71- and 4.4-fold at 0.1 and 10 muM glibenclamide, 2.37- and 3.8-fold at 0.01 and 1 muM repaglinide, and of 3.2- and 4.6- fold at 10 and 1000 muM nateglinide, respectively. Glibenclamide at 0.1 - 10 nM ( doses that were less efficient on insulin secretion) did not induce beta-cell apoptosis after 4 h incubation as well as 0.1 nM after 4 d incubation. However, 1 and 10 nM glibenclamide for 4 d induced a 2.24- and 2.53-fold increase in beta-cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels induces beta-cell apoptosis in human islets and may precipitate the decrease in beta-cell mass observed in patients with type 2 diabetes.