Drug-induced desensitization of insulinotropic actions of sulfonylureas.
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 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).
Ball
A J
AJ
School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland.
McCluskey
J T
JT
Flatt
P R
PR
McClenaghan
N H
NH
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects; D011189:Potassium Chloride / Q000378:metabolism; D051381:Rats; D014044:Tolbutamide / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D006146:Guanidines; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D014044:Tolbutamide; C092674:BTS 67582; C062597:efaroxan; D005947:Glucose