The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide

Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate i nsulin secretion by closing the ATP-sensitive K+ (K-ATP) channels in pancre atic beta -cells. However, its selectivity for the various K-ATP channels i s not known. In this study, we examined the effects of mitiglinide on vario us cloned KATP channels (Kir6.2/SUR1. Kir6.2/SUR2A, and Kir6.2/SUR2B) recon stituted in COS-I cells, and compared them to another meglitinide-related c ompound, nateglinide. Patch-clamp analysis using inside-out recording confi guration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high d oses (more than 10 muM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentratio ns (1 muM). Binding experiments on mitiglinide, nateglinide, and repaglinid e to SUR1 expressed in COS-1 cells revealed that they inhibit the binding o f [H-3]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide , 8 muM; repaglinide, 1.6 muM), suggesting that they all share a glibenclam ide binding site. The insulin responses to glucose, mitiglinide, tolbutamid e, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the s ulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i. e., the pancreatic beta -cell KATP channel, and suggest that mitiglinide ma y be a clinically useful anti-diabetic drug. (C) 2001 Published by Elsevier Science B.V.