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    Drug-induced desensitization of insulinotropic actions of sulfonylureas.

    Date
    2000-04-29
    Author
    Ball, A. J.
    McCluskey, Jane T.
    Flatt, P. R.
    McClenaghan, N. H.
    Metadata
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    Citation
    Ball, A., McCluskey, J., Flatt, P. & McClenaghan, N. (2000) Drug-induced desensitization of insulinotropic actions of sulfonylureas., Biochemical and biophysical research communications, vol. 271, , pp. 234-9,
    Abstract
    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).
    Official URL
    http://dx.doi.org/10.1006/bbrc.2000.2609
    URI
    https://eresearch.qmu.ac.uk/handle/20.500.12289/4509
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    • Dietetics, Nutrition and Biological Sciences

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