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Induced desensitization of the insulinotropic effects of antidiabetic drugs, BTS 67 582 and tolbutamide

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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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Abstract

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
ID Code:3096
Deposited By:Professor Peter Flatt
Deposited On:13 Jan 2010 12:09
Last Modified:15 Jun 2011 11:10

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