Urolithin C increases glucose-induced ERK activation which contributes to insulin secretion

Polyphenols exert pharmacological actions through protein-mediated mechanisms and by modulating intracellular signalling pathways. We recently showed that a gut-microbial metabolite of ellagic acid named urolithin C is a glucose-dependent activator of insulin secretion acting by facilitating L-type Ca²⁺ channel opening and Ca²⁺ influx into pancreatic β-cells. However, it is still unknown whether urolithin C regulates key intracellular signalling proteins in β-cells. Here, we report that urolithin C enhanced glucose-induced extracellular signal-regulated kinases 1/2 (ERK1/2) activation as shown by higher phosphorylation levels in INS-1 β-cells. Interestingly, inhibition of ERK1/2 with two structurally distinct inhibitors led to a reduction in urolithin C effect on insulin secretion. Finally, we provide data to suggest that urolithin C-mediated ERK1/2 phosphorylation involved insulin signalling in INS-1 cells. Together, these data indicate that the pharmacological action of urolithin C on insulin secretion relies, in part, on its capacity to enhance glucose-induced ERK1/2 activation. Therefore, our study extends our understanding of the pharmacological action of urolithin C in β-cells. More generally, our findings revealed that urolithin C modulated the activation of key multifunctional intracellular signalling kinases which participate in the regulation of numerous biological processes.