TY - JOUR
T1 - Drug-induced desensitization of insulinotropic actions of sulfonylureas
AU - Ball, Andrew J.
AU - McCluskey, Jane T.
AU - Flatt, Peter R.
AU - McClenaghan, Neville H.
PY - 2000/4/29
Y1 - 2000/4/29
N2 - K(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 μM) 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, 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 μM) 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.
UR - http://www.scopus.com/inward/record.url?scp=0034728758&partnerID=8YFLogxK
U2 - 10.1006/bbrc.2000.2609
DO - 10.1006/bbrc.2000.2609
M3 - Article
C2 - 10777708
AN - SCOPUS:0034728758
SN - 0006-291X
VL - 271
SP - 234
EP - 239
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -