Sulfonylurea Induced -Cell Apoptosis in Cultured Human Islets

Loss of -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 -cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on -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 M glibenclamide induced a 2.09and 2.46-fold increase in -cell apoptosis, respectively, whereas repaglinide (0.01 and 1 M) did not change the number of apoptotic -cells. At low concentration (10 M), nateglinide did not induce -cell apoptosis. However, at high concentration of 1000 M, it induced a 1.49-fold increase in the number of apoptotic -cells. Prolonged exposure for 4 d of the islets to the secretagogues induced -cell apoptosis. The increase was of 3.71and 4.4-fold at 0.1 and 10 M glibenclamide, 2.37and 3.8-fold at 0.01 and 1 M repaglinide, and of 3.2and 4.6-fold at 10 and 1000 M nateglinide, respectively. Glibenclamide at 0.1–10 nM (doses that were less efficient on insulin secretion) did not induce -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 2.24and 2.53-fold increase in -cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K sulfonylurea receptor subtype of ATP-sensitive potassium channels induces -cell apoptosis in human islets and may precipitate the decrease in -cell mass observed in patients with type 2 diabetes. (J Clin Endocrinol Metab 90: 501–506, 2005)