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Sulfonylurea Induced ß-Cell Apoptosis in Cultured Human Islets

Division of Endocrinology and Diabetes (K.M., R.A.Z., M.Y.D.), University Hospital, CH-8091 Zurich, Switzerland; Novo Nordisk A/S (R.D.C.), 2880 Bagsværd, Denmark; and Department of Surgery (D.B., T.B.), University of Geneva Medical Center, 1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Marc Y. Donath, M.D., Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch.

Loss of ß-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 ß-cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on ß-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 ß-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 µM) did not change the number of apoptotic ß-cells. At low concentration (10 µM), nateglinide did not induce ß-cell apoptosis. However, at high concentration of 1000 µM, it induced a 1.49-fold increase in the number of apoptotic ß-cells. Prolonged exposure for 4 d of the islets to the secretagogues induced ß-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 ß-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 ß-cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K⁺ sulfonylurea receptor subtype of ATP-sensitive potassium channels induces ß-cell apoptosis in human islets and may precipitate the decrease in ß-cell mass observed in patients with type 2 diabetes.

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