McClenaghan, Neville, Ball, AJ and Flatt, Peter (2000) Induced desensitization of the insulinotropic effects of antidiabetic drugs, BTS 67 582 and tolbutamide. BRITISH JOURNAL OF PHARMACOLOGY, 130 (2). pp. 478-484. [Journal article]
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1 Acute and chronic mechanisms of action of novel insulinotropic antidiabetic drug, BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guanidin fumarate), were examined in the stable cultured BRIN-BD11 cell line. 2 BTS67582 (100-400 mu M) stimulated a concentration-dependent increase (P<0.01) in insulin release at both non-stimulatory (1.1 mM) and stimulatory (8.4 mM) glucose. 3 Long-term exposure (3-18 h) to 100 mu M BTS67582 in culture time-dependently decreased subsequent responsiveness to acute challenge with 200 mu M BTS 67 582 or 200 mu M tolbutamide at 12-18 h (P<0.001). Similarly 3-18 h culture with the sulphonylurea, tolbutamide (100 mu M), also effectively suppressed subsequent insulinotropic responses to both BTS 67 582 and tolbutamide. 4 Culture with 100 mu M BTS67582 or 100 mu M tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 mu M of the imidazoline, efaroxan. 5 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 KCI, 25 mu M forskolin or 10 nM phorbol-12-myristate 13-acetate (PMA), significant inhibition (P<0.001) of the insulinotropic effects of 10 mM 3-ketoisocaproic acid (KIC) and 10 mM alanine were observed. 6 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.
|Item Type:||Journal article|
|Faculties and Schools:||Faculty of Life and Health Sciences|
Faculty of Life and Health Sciences > School of Biomedical Sciences
|Research Institutes and Groups:||Biomedical Sciences Research Institute|
Biomedical Sciences Research Institute > Diabetes
|Deposited By:||Professor Peter Flatt|
|Deposited On:||13 Jan 2010 12:09|
|Last Modified:||15 Jun 2011 10:10|
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