Stimulation of insulin release from the MIN6 cell line by a new imidazoline compound, S‐21663: evidence for the existence of a novel imidazoline site in β cells

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Abstract
The MIN6 cell line derived from in vivo immortalized insulin‐secreting pancreatic β cells was used to study the insulin‐releasing capacity and the cellular mode of action of S‐21663, a newly synthesized imadizoline compound known for its antidiabetic effect in vivo and its ability to release insulin from perfused pancreas. S‐21663, at concentrations ranging from 10−5 M to 10−3 M was able to release insulin from MIN6 cells; its activity peaked at 10−4 M, a drop in the stimulant factor being noted between 10−4 and 10−3 M. Its efficacy, which did not differ whatever the glucose concentration (stimulant or not), was higher than that of the other secretagogues tested, glucose, sulphonylureas or the peptide tGLP‐1. In contrast to tGLP‐1, S‐21663 did not change the cyclic AMP content, whereas it increased Ca2+ influx via verapamil‐ and nifedipine‐sensitive voltage‐dependent calcium channels, the insulin release being a direct consequence of this Ca2+ entry. The S‐21663‐induced Ca2+ influx appears to be essentially the consequence of closure of K+ channels which differ from the ATP‐dependent K+ (K‐ATP) channels as determined by measurement of 86Rb efflux and use of a K‐ATP channel opener. Comparison of the effects of S‐21663 to that of efaroxan, another imidazoline compound shown to act on insulin release in a glucose‐dependent way via binding sites distinct from the imidazoline I1 and I2 sites, suggested that S‐21663 acts through a novel site which displays a remarkably stable expression along the cell culture. It is concluded that S‐21663 is a very efficient, glucose‐independent insulin secretagogue acting through a novel imidazoline site, linked to K+ channels, distinct from the I1, I2 and ‘efaroxan’ binding sites. In vitro and in vivo features of S‐21663 indicate that this compound, or new drugs drived from it, might be the basis for a new pharmacological approach to the mangement of type II (non insulin‐dependent) diabetes. British Journal of Pharmacology (1997) 122, 786–791; doi:10.1038/sj.bjp.0701449