Insulin-releasing action of the novel antidiabetic agent BTS 67 582

1. BTS 67 582 (1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate) is a novel 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-stimulating (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 depolarizing concentration of K⁺ (30 mM), whereas the K⁺ channel openers pinacidil (400 μM) and diazoxide (300 μM) inhibited BTS 67 582-induced release. 4. Suppression of Ca⁺ channel activity with verapamil (20 μM) 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 intracellular cyclic AMP concentrations (25 μM forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 μM). 6. Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 μM) was partially reversed by BTS 67 582 (10^-4 M). 7. These data suggest that the insulin-releasing effect of BTS 67 582 involves regulation of ATP-sensitive K⁺ channel activity and Ca²⁺ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67 582 may also exert insulin-releasing effects independently of ATP-sensitive K⁺ channel activity.