title: Investigation of the effects of sulfonylurea exposure on pancreatic beta cell metabolism.
abstract: Prolonged exposure of pancreatic beta cells to the sulfonylureas glibencamide and tolbutamide induces subsequent desensitization to the actions of these drugs. The precise mechanisms underlying this desensitization remain unknown, prompting the present study, which investigated the impact of prolonged sulfonylurea exposure on glucose and energy metabolism using clonal pancreatic BRIN-BD11 beta cells. Following prolonged exposure to tolbutamide, BRIN-BD11 beta cells were incubated in the presence of [U-(13)C]glucose, and isotopomer analysis revealed that there was a change in the ratio of flux through pyruvate carboxylase (EC 6.4.1.1) and pyruvate dehydrogenase (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4). Energy status in intact BRIN-BD11 cells was determined using (31)P-NMR spectroscopy. Exposure to tolbutamide did not alter the nucleotide triphosphate levels. Collectively, data from the present study demonstrate that prolonged exposure of beta cells to tolbutamide results in changes in flux through key enzymes involved in glucose metabolism that, in turn, may impact on glucose-induced insulin secretion.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Ireland. lorraine.brennan@ucd.ie
authors.forename: Lorraine
authors.initials: L
authors.lastname: Brennan
authors.forename: Chandralal
authors.initials: C
authors.lastname: Hewage
authors.forename: J P G
authors.initials: JP
authors.lastname: Malthouse
authors.forename: Neville H
authors.initials: NH
authors.lastname: McClenaghan
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D014044:Tolbutamide; D005947:Glucose; D005905:Glyburide