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 insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration 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 doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, 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 sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.
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Mitiglinide [3H]glibenclamide ATP mitiglinide nateglinide repaglinide glibenclamide K+ K glucose mitiglinide ATP tolbutamide glibenclamide KAD-1229 mitiglinide nateglinide repaglinide tolbutamide glibenclamide sulfonylureas mitiglinide K ATP mitiglinide K ATP mitiglinide K ATP meglitinide nateglinide mitiglinide Nateglinide mitiglinide nateglinide repaglinide sulfonylureas mitiglinide nateglinide KAD-1229 ATP-sensitive K+ (K(ATP)) channels SUR1 insulin Kir6.2 SUR1 K(ATP) channel K(ATP) channels K(ATP) channels Kir6.2 SUR1 Kir6.2 SUR2A Kir6.2 SUR2B Kir6.2 SUR1 Kir6.2 SUR2A Kir6.2 SUR2B insulin Kir6.2 SUR1 Kir6.2 SUR2B Kir6.2 SUR2A SUR1 ATP-sensitive K+ channels insulin