tailieunhanh - Báo cáo khoa học: Investigation of the effects of sulfonylurea exposure on pancreatic beta cell metabolism

Prolonged exposure of pancreatic beta cells to the sulfonylureas glibenca-mide 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. | ễFEBS Journal Investigation of the effects of sulfonylurea exposure on pancreatic beta cell metabolism Lorraine Brennan1 Chandralal Hewage1 J. P. G. Malthouse1 Neville H. McClenaghan2 Peter R. Flatt2 and Philip Newsholme1 1 UCD Schoolof Biomolecular and BiomedicalScience UCD Conway Institute University College Dublin Belfield Ireland 2 Schoolof BiomedicalSciences University of Ulster Coleraine UK Keywords beta cells metabolism sulfonylurea Correspondence L. Brennan UCD Schoolof Biomolecular and BiomedicalScience UCD Conway Institute University College Dublin Belfield Dublin 4 Ireland Fax 353 1 2837211 Tel 353 1 7166781 E-mail Received 9 June 2006 revised 21 September 2006 accepted 22 September 2006 doi Prolonged exposure of pancreatic beta cells to the sulfonylureas glibenca-mide 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-13C glucose and isotopomer analysis revealed that there was a change in the ratio of flux through pyruvate carboxylase EC and pyruvate dehydrogenase EC EC EC . Energy status in intact BRIN-BD11 cells was determined using 31P-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. Sulfonylureas are a major class of potent insulinotrop-ic drugs that are used extensively in the treatment of patients with type 2