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

• Published in: European journal of pharmacology 2001-11, Vol.431 (1), p.119-125
• Main Authors: Sunaga, Yasuhiro, Gonoi, Tohru, Shibasaki, Tadao, Ichikawa, Kiyoshi, Kusama, Hiroshi, Yano, Hideki, Seino, Susumu
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters; Biological and medical sciences; Cell Line; COS Cells; Cyclohexanes - pharmacology; General and cellular metabolism. Vitamins; Glyburide - pharmacology; Hypoglycemic Agents - pharmacology; Indoles - pharmacology; Insulin - metabolism; Insulin secretion; Isoindoles; K ATP channel; Medical sciences; Mitiglinide; Nateglinide; Patch-Clamp Techniques; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Receptors, Drug - genetics; Receptors, Drug - metabolism; Sulfonylurea Compounds - pharmacology; Sulfonylurea receptor (SUR); Sulfonylurea Receptors; Tolbutamide - pharmacology; Transfection
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01412-1

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 β-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 (IC 50 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 μM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 μM). 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 (IC 50 values: mitiglinide, 280 nM; nateglinide, 8 μM; repaglinide, 1.6 μM), 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 β-cell K ATP channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.