Introduction: b-cell function and in particular glucose-induced insulin secretion play a crucial role in glucose homeostasis. We previously described that the flavonoid quercetin potentiates glucose-induced insulin secretion through a mechanism implicating the activation of L-type Calcium (CaV) channels and ERK 1/2 kinase [1,2]. Based on a study showing that plant flavonoids differently modulate vascular CaV channels [3], we analyzed the capacity of quercetin-like compounds to modulate insulin secretion, and studied their underlying mechanisms. Material and methods: Experiments were performed in both INS-1 b-cell line and rat isolated pancreatic islets. Insulin release was quantified by the homogeneous time-resolved fluorescence (HTRF) method and ERK1/2 activation was examined by western blot experiments. Calcium channel currents were recorded with the whole-cell patch-clamp technique, and intracellular calcium was measured with the fluorescent calcium indicator Fluo4. Mitochondrial respiration was measured by high-resolution respirometry (OROBOROS). Results: Among eight compounds tested, we selected resokaempferol, morin and galangin on the basis of their different pharmacological behavior on glucose-stimulated insulin secretion. Despite closely-related structures, resokaempferol potentiated glucose-induced insulin secretion both in INS-1 cells and in rat isolated pancreatic islets whereas galangin had the opposite effect and morin was ineffective. Regarding the mechanism of action, we evaluated how these polyphenols regulate specific pathways, particularly important for b-cell function (intracellular calcium concentration, calcium channel activation, protein kinase activation and mitochondrial respiration). Discussion/Conclusion: As resokaempferol and galangin differ from the position of a single hydroxy group borne by carbon C40 and C5 respectively, these functions are likely to be determinant for quercetin-like compound activity. This hypothesis will be further investigated. In addition, our data suggested that resokaempferol exerts favorable pharmacological action on glucose-stimulated insulin secretion. References [1] Youl E. et al. Br. J. Pharmacol.(2010) 161 799–814. [2] Bardy G. et al. Br. J. Pharmacol. (2013) 169 1102–1113. [3] Saponara S. et al. Br. J. Pharmacol. (2011) 164 1684–1697.