title: Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of K(ATP) channel components.
abstract: Clonal insulin-secreting BRIN-BD11 cells were used to examine effects of chronic 72-144 h exposure to the sulphonylureas tolbutamide and glibenclamide on insulin release, cellular insulin content, and mRNA levels of the Kir6.2 and SUR1 subunits of the beta-cell K(ATP) channel. Chronic exposure for 72-144 h to 5-100 microM tolbutamide and glibenclamide resulted in a time- and concentration-dependent irreversible decline in sulphonylurea-induced insulin secretion. In contrast, the decline in cellular insulin content induced by chronic exposure to high concentrations of sulphonylureas was readily reversible. Chronic exposure to tolbutamide or glibenclamide had no effect upon transcription of the Kir6.2 or SUR1 subunits of the pancreatic beta-cell K(ATP) channel. Whilst further studies are required to understand the precise nature of the chronic interactions of sulphonylurea with the insulin exocytotic mechanism, these observations may partially explain the well-known progressive failure of sulphonylurea therapy in type 2 diabetes.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. ajball@ucsd.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ball
authors.forename: Jane T
authors.initials: JT
authors.lastname: McCluskey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Neville H
authors.initials: NH
authors.lastname: McClenaghan
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002478:Cells, Cultured; D002999:Clone Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011955:Receptors, Drug; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology*; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat