In vitro mechanism of action on insulin release of S-22068, a new putativeantidiabetic compound

1 The MIN6 cell line derived from in vivo immortalized insulin-secreting pa ncreatic beta cells was used to study the insulin-releasing capacity and th e cellular mode of action of S-22068, a newly synthesized imidazoline compo und known for its antidiabetic effect in vivo. 2 S-22068, was able to release insulin from MIN6 cells in a dose-dependent manner with a half-maximal stimulation at 100 mu M. Its efficacy (8 fold ov er the basal value), which did not differ whatever the glucose concentratio n (stimulatory or not), was intermediate between that of sulphonylurea and that of efaroxan. 3 Similarly to sulphonylureas and classical imidazolines, S-22068 blocked K -ATP channels and, in turn, opened nifedipine-sensitive voltage-dependent C a2+ channels, triggering Ca2+ entry. 4 Similarly to other imidazolines, S-22068 induced a closure of cloned K-AT P channels injected to Xenopus oocytes by interacting with the pore-forming Kir6.2 moiety. 5 S-22068 did not interact with the sulphonylurea binding site nor with the non-I-1 and non-I-2 imidazoline site evidenced in the beta cells that is r ecognized by the imidazoline compounds efaroxan, phentolamine and RX821002. 6 We conclude that S-22068 is a novel imidazoline compound which stimulates insulin release via interaction with an original site present on the Kir6. 2 moiety of the beta cell K-ATP channels.