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Submitted on April 13, 2004
Accepted on October 4, 2004
-cell apoptosis in cultured human islets
Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland; Novo Nordisk A/S, Bagsværd, Denmark; Department of Surgery, University of Geneva Medical Center, Geneva, Switzerland
* To whom correspondence should be addressed.
Marc Y. Donath, E-mail: marc.donath{at}usz.ch
Loss of 
-cell mass and function raises a concern regarding the application of sulfonylureas for the treatment of type 2 diabetes, since previous studies have shown that agents that cause closure of Kir 6.2 SUR1 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 of 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 µM glibenclamide induced a 2.09- and 2.46-fold increase in -cell apoptosis, respectively, whereas repaglinide (0.01 and 1 µM) did not change the number of apoptotic -cells. At low concentration (10 µM), nateglinide did not induce -cell apoptosis. However, at high concentration of 1000 µM, 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 3.71- 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 which 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 2.24- and 2.53-fold increase in -cell apoptosis, respectively. Taken together, closure of the Kir 6.2 SUR1 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.
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