Background and Purpose: The pharmacology of flavonoids on β-cell function is largely undefined especially in the context of defective secretion of insulin. We sought to identify flavonoids that increased the insulin-secreting function of β-cells and to explore the underlying mechanisms.
Experimental Approach: INS-1 β-cells in culture and islets of Langerhans isolated from control and diabetic male rats were used for insulin secretion experiments. Pharmacological and electrophysiological approaches were used for mechanistic studies.
Key Results: Among a set of flavonoids, exposure of INS-1 β-cells to resokaempferol (ResoK) enhanced glucose-stimulated insulin secretion and therefore we further char- acterised its activity and its pharmacological mechanism. ResoK glucose-dependently enhanced insulin secretion in INS-1 β-cells and pancreatic islets isolated from rats. Mechanistically, whole cell patch clamp recordings in INS-1 cells showed that ResoK rapidly and dose-dependently enhanced the L-type Ca2+ current whereas it was inac- tive towards T-type Ca2+ current. Accordingly, pharmacological inhibition of L-type Ca2+ current but not T-type Ca2+ current blocked the effects of ResoK on glucose- stimulated insulin secretion. ResoK was still active on dysfunctional β-cells as it ame- liorated glucose-stimulated insulin secretion in glucotoxicity-induced dysfunctional INS-1 cells and in pancreatic islets isolated from diabetic rats.
Conclusion and Implications: ResoK is a glucose-dependent activator of insulin secretion. Our results indicated that the effects of ResoK on insulin secretion involved its capacity to stimulate L-type Ca2+ currents in cultured β-cells. As ResoK was also effective on dysfunctional β-cells, our work provides a new approach to stimulating insulin secretion, using compounds based on the structure of ResoK.

flavonoid, resokaempferol, insulin secretion, pancreatic β-cells