title: Novel I1-Imidazoline Agonist S43126 Augment Insulin Secretion in Min6 Cells.
abstract: The I1-imidazoline receptor is a novel drug target for hypertension and insulin resistance which are major disorders associated with Type II diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126 on calcium fluxes and insulin secretion from Min6 β-cells. We also examined the effects of S43126 on the induction of IRAS, and phosphorylation of components in the I1-imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10-8M to 10-5M] for various time (5-60mins). S43126 at higher dose [10-5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+influx mediated by S43126 [10-5M] were decreased following co-treatment with efaroxan (I1-antagonist) and nifedipine (L-type voltage-gated Ca2+-channel blocker) at various times (5-60mins). Furthermore, S43126 at [10-5M] increased Ca2+oscillation, [Ca2+] and45Ca2+uptake in a time and dose-dependent manner. Moreover, Western blot analysis of treated samples showed that S43126 caused an increased protein expression of IRAS as well as phosphorylation of both ERK1/2 and PKB in a concentration-dependent manner. We conclude that S43126 exerts its insulinotropic effect in a glucose dependent manner by a mechanism involving L-type calcium channels and imidazoline I1-receptors.
authors.affiliation: Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Jerusalem
authors.initials: J
authors.lastname: Tesfai
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Universite Paul Sabatier, Faculté de Pharmacie, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Crane
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Universite Paul Sabatier, Faculté de Pharmacie, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Baziard-Mouysset
authors.affiliation: Center for Dental Research, School of Dentistry and School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Lincoln P
authors.initials: LP
authors.lastname: Edwards