Study of the Insulinotropic Effect of the Novel Antihyperglycemic Agent KAD-1229 Using HIT T15 Cells, a Hamster’s Insulinoma Cell Line

The insulinotropic effect of (+)- monocal-cium bis [(2S)-2-benzyl-3-(cis-hexahydro-2- isoindolinyl-carbonyl) propionate] dihy-drate (CAS 145375-43-5, KAD-1229) was assessed by comparing it with those of glibenclamide (CAS 10238-21-8), nategli-nide (CAS 105816-04-4), and repaglinide (CAS 135062-02-1) using HIT T15 cells, a hamster insulinoma cell line. Although their potencies were different, KAD-1229, glibenclamide, nateglinide, and repaglinide all concentration-dependently and significantly induced insulin release from these cells. Further, each agent displaced the binding of 3 H-glibenclamide to the cell membrane and inhibited 86 Rb + efflux from the cells. These results indicate that KAD-1229, glibenclamide, nateglinide, and repaglinide each exert their insulinotropic effect by binding to the glibenclamide binding sites (sulfonylurea receptors) on pancreatic s-cells and closing K + channels. Diazoxide, a K + channel opener, and nitrendipine, a Ca 2+ blocker, suppressed the insulin release induced by KAD-1229 or glibenclamide. These results demonstrate that the insulinotropic actions of KAD-1229 and glibenclamide involve similar underlying pathways.