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The I 1 -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 I 1 -imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10 -8 M to 10 -5 M] for various time (5-60mins). S43126 at higher dose [10 -5 M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca 2+ influx mediated by S43126 [10 -5 M] were decreased following co-treatment with efaroxan (I 1 -antagonist) and nifedipine (L-type voltage-gated Ca 2+ -channel blocker) at various times (5-60mins). Furthermore, S43126 at [10 -5 M] increased Ca 2+ oscillation, [Ca 2+ ] and 45 Ca 2+ 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 I 1 -receptors.

Novel I1-Imidazoline Agonist S43126 Augment Insulin Secretion in Min6 Cells