Drug-induced desensitization of insulinotropic actions of sulfonylureas

AJ Ball, Janie McCluskey, Peter Flatt, Neville McClenaghan

Research output: Contribution to journalArticle

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Abstract

K-ATP-channel-dependent and K-ATP-channel-independent insulin-releasing actions of the sulfonylurea, tolbutamide, mere examined in the clonal BRIN-BD11 cell line. Tolbutamide stimulated insulin release at both nonstimulatory (1.1 mM) and stimulatory (16.7 mM) glucose. Under depolarizing conditions (16.7 mM glucose plus 30 mM KCl) tolbutamide evoked a stepwise K-ATP channel-independent insulinotropic response. Culture (18 h) with tolbutamide or the guanidine derivative BTS 67 582 (100 mu M) markedly reduced (P <0.001) subsequent responsiveness to acute challenge with tolbutamide, glibenclamide, and BTS 67 582 but not the imidazoline drug, efaroxan. Conversely, 18 h culture with efaroxan reduced (P <0.001) subsequent insulinotropic effects of efaroxan but not that of tolbutamide, glibenclamide, or BTS 67 582. Culture (18 h) with tolbutamide reduced the K-ATP channel-independent actions of both tolbutamide and glibenclamide. Whereas culture with efaroxan exerted no effect on the K-ATP channel-independent actions of sulfonylureas, BTS 67 582 abolished the response of tolbutamide and inhibited that of glibenclamide. These data demonstrate that prolonged exposure to tolbutamide desensitizes both K-ATP-channel-dependent and -independent insulin-secretory actions of sulfonylureas, indicating synergistic pathways mediated by common sulfonylurea binding site(s). (C) 2000 Academic Press.
LanguageEnglish
Pages234-239
JournalBiochemical and Biophysical Research Communications
Volume271
Issue number1
Publication statusPublished - Apr 2000

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Tolbutamide
efaroxan
Pharmaceutical Preparations
Glyburide
Adenosine Triphosphate
Insulin
Imidazolines
Glucose
Guanidine
Binding Sites
Cell Line

Cite this

Ball, AJ., McCluskey, J., Flatt, P., & McClenaghan, N. (2000). Drug-induced desensitization of insulinotropic actions of sulfonylureas. 271(1), 234-239.
Ball, AJ ; McCluskey, Janie ; Flatt, Peter ; McClenaghan, Neville. / Drug-induced desensitization of insulinotropic actions of sulfonylureas. 2000 ; Vol. 271, No. 1. pp. 234-239.
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Ball, AJ, McCluskey, J, Flatt, P & McClenaghan, N 2000, 'Drug-induced desensitization of insulinotropic actions of sulfonylureas', vol. 271, no. 1, pp. 234-239.

Drug-induced desensitization of insulinotropic actions of sulfonylureas. / Ball, AJ; McCluskey, Janie; Flatt, Peter; McClenaghan, Neville.

Vol. 271, No. 1, 04.2000, p. 234-239.

Research output: Contribution to journalArticle

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T1 - Drug-induced desensitization of insulinotropic actions of sulfonylureas

AU - Ball, AJ

AU - McCluskey, Janie

AU - Flatt, Peter

AU - McClenaghan, Neville

PY - 2000/4

Y1 - 2000/4

N2 - K-ATP-channel-dependent and K-ATP-channel-independent insulin-releasing actions of the sulfonylurea, tolbutamide, mere examined in the clonal BRIN-BD11 cell line. Tolbutamide stimulated insulin release at both nonstimulatory (1.1 mM) and stimulatory (16.7 mM) glucose. Under depolarizing conditions (16.7 mM glucose plus 30 mM KCl) tolbutamide evoked a stepwise K-ATP channel-independent insulinotropic response. Culture (18 h) with tolbutamide or the guanidine derivative BTS 67 582 (100 mu M) markedly reduced (P <0.001) subsequent responsiveness to acute challenge with tolbutamide, glibenclamide, and BTS 67 582 but not the imidazoline drug, efaroxan. Conversely, 18 h culture with efaroxan reduced (P <0.001) subsequent insulinotropic effects of efaroxan but not that of tolbutamide, glibenclamide, or BTS 67 582. Culture (18 h) with tolbutamide reduced the K-ATP channel-independent actions of both tolbutamide and glibenclamide. Whereas culture with efaroxan exerted no effect on the K-ATP channel-independent actions of sulfonylureas, BTS 67 582 abolished the response of tolbutamide and inhibited that of glibenclamide. These data demonstrate that prolonged exposure to tolbutamide desensitizes both K-ATP-channel-dependent and -independent insulin-secretory actions of sulfonylureas, indicating synergistic pathways mediated by common sulfonylurea binding site(s). (C) 2000 Academic Press.

AB - K-ATP-channel-dependent and K-ATP-channel-independent insulin-releasing actions of the sulfonylurea, tolbutamide, mere examined in the clonal BRIN-BD11 cell line. Tolbutamide stimulated insulin release at both nonstimulatory (1.1 mM) and stimulatory (16.7 mM) glucose. Under depolarizing conditions (16.7 mM glucose plus 30 mM KCl) tolbutamide evoked a stepwise K-ATP channel-independent insulinotropic response. Culture (18 h) with tolbutamide or the guanidine derivative BTS 67 582 (100 mu M) markedly reduced (P <0.001) subsequent responsiveness to acute challenge with tolbutamide, glibenclamide, and BTS 67 582 but not the imidazoline drug, efaroxan. Conversely, 18 h culture with efaroxan reduced (P <0.001) subsequent insulinotropic effects of efaroxan but not that of tolbutamide, glibenclamide, or BTS 67 582. Culture (18 h) with tolbutamide reduced the K-ATP channel-independent actions of both tolbutamide and glibenclamide. Whereas culture with efaroxan exerted no effect on the K-ATP channel-independent actions of sulfonylureas, BTS 67 582 abolished the response of tolbutamide and inhibited that of glibenclamide. These data demonstrate that prolonged exposure to tolbutamide desensitizes both K-ATP-channel-dependent and -independent insulin-secretory actions of sulfonylureas, indicating synergistic pathways mediated by common sulfonylurea binding site(s). (C) 2000 Academic Press.

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Ball AJ, McCluskey J, Flatt P, McClenaghan N. Drug-induced desensitization of insulinotropic actions of sulfonylureas. 2000 Apr;271(1):234-239.