Drug-induced desensitization of insulinotropic actions of sulfonylureas

K-ATP-channel-dependent and K-ATP-channel-independent insulin-releasing act ions of the sulfonylurea, tolbutamide, mere examined in the clonal BRIN-BD1 1 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 th e guanidine derivative BTS 67 582 (100 mu M) markedly reduced (P < 0.001) s ubsequent responsiveness to acute challenge with tolbutamide, glibenclamide , and BTS 67 582 but not the imidazoline drug, efaroxan. Conversely, 18 h c ulture with efaroxan reduced (P < 0.001) subsequent insulinotropic effects of efaroxan but not that of tolbutamide, glibenclamide, or BTS 67 582. Cult ure (18 h) with tolbutamide reduced the K-ATP channel-independent actions o f both tolbutamide and glibenclamide. Whereas culture with efaroxan exerted no effect on the K-ATP channel-independent actions of sulfonylureas, BTS 6 7 582 abolished the response of tolbutamide and inhibited that of glibencla mide. These data demonstrate that prolonged exposure to tolbutamide desensi tizes both K-ATP-channel-dependent and -independent insulin-secretory actio ns of sulfonylureas, indicating synergistic pathways mediated by common sul fonylurea binding site(s). (C) 2000 Academic Press.