Previous studies have shown that prolonged exposure to drugs, which act via blocking K-ATP channels, can desensitize the insulinotropic effects of drugs and nutrients acting via K-ATP channels. in this study, effects of prolonged exposure to diazoxide, a K-ATP channel opener, on beta cell function were examined using clonal BRIN-BD11 cells. The findings were compared to the long-term effects of K-ATP channel blockers nateglinide and tolbutamide. Following 18 h exposure to 200 muM diazoxide, the amounts of insulin secreted in response to glucose, amino acids and insulinotropic drugs were increased. Secretory responsiveness to a variety of agents acting via K-ATP channels was retained following, prolonged diazoxide exposure. In contrast, 18 h exposure to 100 muM nateglinide significantly attenuated the insulin secretory responses to tolbutamide, nateglinide and BTS 67 582. Glucose- and L-alanine-stimulated insulin release were unaffected by prolonged nateglinide exposure, however responsiveness to L-leucine and L-arginine was diminished. Prolonged exposure to nateglinide had no effect on forskolin- and PMA-stimulated insulin release, and the overall pattern of desensitization was similar to that induced by 100 muM tolbutamide. We conclude that in contrast to chronic long-term K-ATP channel blockade, long-term diazoxide treatment is not harmful to K-ATP channel mediated insulin secretion and may have beneficial protective effects on beta cell function. (C) 2004 Elsevier Inc. All rights reserved.