Alterations of insulin secretion following long-term manipulation of ATP-sensitive potassium channels by diazoxide and nateglinide

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 μM 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 μM 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 μM 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.