Development of new hypoglycemic agents with a novel insulinotropic mechanism and their clinical appkicatior

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The effect of metabolic inhibition on the blocking of beta cell ATP-sensitive K^+ channels (K_<ATP> channels) by glibenclamide was investigated using patch-clamp technique. Inhibition of K_<ATP> channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1muM) of ATP applied in the inside-out mode, K_<ATP> channel activity was not fully abolished even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete K_<ATP> channel inhibition under 10muM ATP.On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits K_<ATP> channel activity in a dose-dependent manner, and completely blocks it even under metabolic inhibition. In sulfonylurea receptor (SUR1)-and inward rectifier K^+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, K_<ATP> channel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic beta cells, probably due to a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.