INSULIN-RELEASING ACTION OF THE NOVEL ANTIDIABETIC AGENT BTS-67-582

1 BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guan fumarate) is a n ovel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN- BD11. 2 BTS 67 582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10(-8) to 10(-4) M) at both non-stimu lating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3 BTS 67 582 (10(-4) M) potentiated the insulin-releasing effect of a d epolarizing concentration of K+ (30 mM), whereas the K+ channel opener s pinacidil (400 mu M) and diazoxide (300 mu M) inhibited BTS 67 582-i nduced release. 4 Suppression of Ca+ channel activity with verapamil ( 20 mu M) reduced the insulin-releasing effect of BTS 67 582 (10(-4) M) . 5 BTS 67 582 (10(-4) M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM). or agents which raise i ntracellular cyclic AMP concentrations (25 mu M forskolin and 1 mM iso butylmethylxanthine), or the cholinoceptor agonist carbachol (100 mu M ). 6 Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 mu M) was partially reversed by BTS 67 582 (10(-4) M). 7 These data suggest that the insulin-releasing effect of BTS 67 5 82 involves regulation of ATP-sensitive K+ channel activity and Ca2+ i nflux, and that the drug augments the stimulant effects of nutrient in sulin secretagogues and agents which enhance adenylate cyclase and pho spholipase C. BTS 67 582 may also exert insulin-releasing effects inde pendently of ATP-sensitive K+ channel activity.