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

1 Acute and chronic mechanisms of action of novel insulinotropic antidiabet ic 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-dependen tly decreased subsequent responsiveness to acute challenge with 200 mu M BT S 67 582 or 200 mu M tolbutamide at 12-18 h (P<0.001). Similarly 3-18 h cul ture with the sulphonylurea, tolbutamide (100 mu M), also effectively suppr essed subsequent insulinotropic responses to both BTS 67 582 and tolbutamid e. 4 Culture with 100 mu M BTS67582 or 100 mu M tolbutamide did not affect bas al insulin secretion, cellular insulin content, or cell viability and exert ed no influence on the secretory responsiveness to 200 mu M of the imidazol ine, efaroxan. 5 While 18 h BTS 67 582 culture did not affect the insulin-releasing action s (P<0.001) of 16.7 mM glucose, 10 mM arginine, 30 mM KCI, 25 mu M forskoli n 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 esta blished insulinotropic antidiabetic agents.