Article date: May 2000
By: Neville H McClenaghan, Andrew J Ball, Peter R Flatt in Volume 130, Issue 2, pages 478-484
Acute and chronic mechanisms of action of novel insulinotropic antidiabetic drug, BTS 67 582 (1,1‐dimethyl‐2‐(2‐morpholinophenyl)guanidine fumarate), were examined in the stable cultured BRIN‐BD11 cell line.
BTS 67 582 (100–400 μM) stimulated a concentration‐dependent increase (P<0.01) in insulin release at both non‐stimulatory (1.1 mM) and stimulatory (8.4 mM) glucose.
Long‐term exposure (3–18 h) to 100 μM BTS 67 582 in culture time‐dependently decreased subsequent responsiveness to acute challenge with 200 μM BTS 67 582 or 200 μM tolbutamide at 12–18 h (P<0.001). Similarly 3–18 h culture with the sulphonylurea, tolbutamide (100 μM), also effectively suppressed subsequent insulinotropic responses to both BTS 67 582 and tolbutamide.
Culture with 100 μM BTS 67 582 or 100 μM tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 μM of the imidazoline, efaroxan.
While 18 h BTS 67 582 culture did not affect the insulin‐releasing actions (P<0.001) of 16.7 mM glucose, 10 mM arginine, 30 mM KCl, 25 μM forskolin or 10 nM phorbol‐12‐myristate 13‐acetate (PMA), significant inhibition (P<0.001) of the insulinotropic effects of 10 mM 2‐ketoisocaproic acid (KIC) and 10 mM alanine were observed.
These data suggest that BTS 67 582 shares a common signalling pathway to sulphonylurea but not imidazoline drugs. Desensitization of drug action may provide an important approach to dissect sites of action of novel and established insulinotropic antidiabetic agents.
Acute and chronic mechanisms of action of novel insulinotropic antidiabetic drug, BTS 67 582 (1,1‐dimethyl‐2‐(2‐morpholinophenyl)guanidine fumarate), were examined in the stable cultured BRIN‐BD11 cell line.
BTS 67 582 (100–400 μM) stimulated a concentration‐dependent increase (P<0.01) in insulin release at both non‐stimulatory (1.1 mM) and stimulatory (8.4 mM) glucose.
Long‐term exposure (3–18 h) to 100 μM BTS 67 582 in culture time‐dependently decreased subsequent responsiveness to acute challenge with 200 μM BTS 67 582 or 200 μM tolbutamide at 12–18 h (P<0.001). Similarly 3–18 h culture with the sulphonylurea, tolbutamide (100 μM), also effectively suppressed subsequent insulinotropic responses to both BTS 67 582 and tolbutamide.
Culture with 100 μM BTS 67 582 or 100 μM tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 μM of the imidazoline, efaroxan.
While 18 h BTS 67 582 culture did not affect the insulin‐releasing actions (P<0.001) of 16.7 mM glucose, 10 mM arginine, 30 mM KCl, 25 μM forskolin or 10 nM phorbol‐12‐myristate 13‐acetate (PMA), significant inhibition (P<0.001) of the insulinotropic effects of 10 mM 2‐ketoisocaproic acid (KIC) and 10 mM alanine were observed.
These data suggest that BTS 67 582 shares a common signalling pathway to sulphonylurea but not imidazoline drugs. Desensitization of drug action may provide an important approach to dissect sites of action of novel and established insulinotropic antidiabetic agents.
British Journal of Pharmacology (2000) 130, 478–484; doi:10.1038/sj.bjp.0703306
DOI: 10.1038/sj.bjp.0703306
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