Sulfonylurea induced β-cell apoptosis in cultured human islets

Abstract

Loss of β-cell mass and function raises a concern regarding the application of sulfonylareas 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 β-cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on β-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 μM glibenclamide induced a 2.09- and 2.46-fold increase in β-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 μM) did not change the number of apoptotic β-cells. At low concentration (10 μM), nateglinide did not induce β-cell apoptosis. However, at high concentration of 1000 μM, it induced a 1.49-fold increase in the number of apoptotic β-cells. Prolonged exposure for 4 d of the islets to the secretagogues induced β-cell apoptosis. The increase was of 3.71- and 4.4-fold at 0.1 and 10 μM glibenclamide, 2.37- and 3.8-fold at 0.01 and 1 μM repaglinide, and of 3.2- and 4.6-fold at 10 and 1000 μM nateglinide, respectively. Glibenclamide at 0.1-10 nM (doses that were less efficient on insulin secretion) did not induce β-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 β-cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K+ sulfonylurea receptor subtype of ATP-sensitive potassium channels induces β-cell apoptosis in human islets and may precipitate the decrease in β-cell mass observed in patients with type 2 diabetes.