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

Laurence Le Brigand; Anne Virsolvy; Dominique Manechez; Jean-Jacques Godfroid; Beatrice Guardiola-Lemaître; Fiona M Gribble; Frances M Ashcroft; Dominique Bataille

doi:10.1038/sj.bjp.0702883

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

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

Laurence Le Brigand, Anne Virsolvy, Dominique Manechez, Jean-Jacques Godfroid, Beatrice Guardiola-Lemaître, Fiona M Gribble, Frances M Ashcroft et Dominique Bataille

British journal of pharmacology, Vol.128(5), pp.1021-1026

11/1999

DOI: https://doi.org/10.1038/sj.bjp.0702883

PMID: 10556939

Résumé

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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-22068, a newly synthesized imidazoline compound known for its antidiabetic effect in vivo.S-22068, was able to release insulin from MIN6 cells in a dose-dependent manner with a half-maximal stimulation at 100 μM. Its efficacy (8 fold over the basal value), which did not differ whatever the glucose concentration (stimulatory or not), was intermediate between that of sulphonylurea and that of efaroxan.Similarly to sulphonylureas and classical imidazolines, S-22068 blocked KATP channels and, in turn, opened nifedipine-sensitive voltage-dependent Ca2+ channels, triggering Ca2+ entry.Similarly to other imidazolines, S-22068 induced a closure of cloned KATP channels injected to Xenopus oocytes by interacting with the pore-forming Kir6.2 moiety.S-22068 did not interact with the sulphonylurea binding site nor with the non-I1 and non-I2 imidazoline site evidenced in the β cells that is recognized by the imidazoline compounds efaroxan, phentolamine and RX821002.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 β cell KATP channels.

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Titre: In vitro mechanism of action on insulin release of S-22068, a new putative antidiabetic compound
Créateurs - sans rôle: Laurence Le Brigand - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Anne Virsolvy - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Dominique Manechez - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Jean-Jacques Godfroid - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Beatrice Guardiola-Lemaître - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Fiona M Gribble - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Frances M Ashcroft - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Dominique Bataille - INSERM U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France Laboratoire de Pharmacochimie Moléculaire, Université Paris VII-Denis Diderot, 75251 Paris Cedex 05, France University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K
Détails de publication: British journal of pharmacology, Vol.128(5), pp.1021-1026
Nombre de pages: 6
Identifiants: 99148709709311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article