Ball, A. J.McCluskey, Jane T.Flatt, P. R.McClenaghan, N. H.2018-06-292018-06-292000-04-29Ball, A.J., McCluskey, J.T., Flatt, P.R. and McClenaghan, N.H. (2000) ‘Drug-induced desensitization of insulinotropic actions of sulfonylureas’, Biochemical and Biophysical Research Communications, 271(1), pp. 234–239. Available at: https://doi.org/10.1006/bbrc.2000.2609.0006-291Xhttps://doi.org/10.1006/bbrc.2000.2609https://eresearch.qmu.ac.uk/handle/20.500.12289/4509K(ATP)-channel-dependent and K(ATP)-channel-independent insulin-releasing actions of the sulfonylurea, tolbutamide, were 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 microM) 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).234-9articlehttp://10.1006/bbrc.2000.2609