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Investigation of the effects of sulfonylurea exposure on pancreatic beta cell metabolism
Author(s) -
Brennan Lorraine,
Hewage Chandralal,
Malthouse J. P. G.,
McClenaghan Neville H.,
Flatt Peter R.,
Newsholme Philip
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05513.x
Subject(s) - tolbutamide , sulfonylurea , beta cell , medicine , pyruvate dehydrogenase complex , endocrinology , chemistry , carbohydrate metabolism , metabolism , pyruvate carboxylase , insulin , enzyme , biology , biochemistry , islet
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.