Sulfonylurea induced beta-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 microm glibenclamide induced a 2.09- and 2.46-fold increase in beta-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 microm) did not change the number of apoptotic beta-cells. At low concentration (10 microm), nateglinide did not induce beta-cell apoptosis. However, at high concentration of 1000 microm, 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 microm glibenclamide, 2.37- and 3.8-fold at 0.01 and 1 microm repaglinide, and of 3.2- and 4.6-fold at 10 and 1000 microm 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.
Maedler
Kathrin
K
Division of Endocrinology and Diabetes, University Hospital, CH-8091 Zurich, Switzerland.
Carr
Richard D
RD
Bosco
Domenico
D
Zuellig
Richard A
RA
Berney
Thierry
T
Donath
Marc Y
MY
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D008875:Middle Aged; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology
D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; D005905:Glyburide; D002118:Calcium