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

Abstract

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.

A mechanistic insight into the biological activities of urolithins as gut microbial metabolites of ellagitannins

“…This effect was induced by regulating cell surface proteins and intracellular signaling pathways including facilitation in L‐type Ca 2+ channel opening and the Ca 2+ influx into INS‐1 cells (Bayle et al, 2019). In 2020, Toubal et al (2020) demonstrated that UroC activated ERK1/2 by phosphorylation in INS‐1 b‐cells. Furthermore, modulation in kinases signaling may be responsible for numerous biological processes.…”

Urolithin C alleviates pancreatic β-cell dysfunction in type 1 diabetes by activating Nrf2 signaling

“…Bayle and colleagues identified UC as a glucose-dependent activator of insulin secretion through upregulation of calcium flux into pancreatic β-cells [ 17 ]. A further study demonstrated that UC enhanced insulin secretion of β-cells via enhancing glucose-induced activation of the ERK signaling, a key intracellular signaling [ 32 ]. These two studies suggest the potential effects of UC on restraining T1D progression via increasing insulin secretion of β-cells but do not provide any direct in vivo evidence.…”

Biocatalytic Approaches for an Efficient and Sustainable Preparation of Polyphenols and Their Derivatives

“…Bayle and co-workers studied the effect of polyphenols on pancreatic β-cell functions and pointed out that urolithin C is a glucose-dependent activator of insulin secretion through the activation of L-type Ca 2+ channels. , Consequently, the pharmacological activity of urolithin C could be beneficial in the treatment of type 2 diabetes . Further studies demonstrate that urolithin C also affects the triggering of intracellular signaling proteins influencing the β-cell function, especially the insulin secretion . Urolithin A has also a valuable effect in the glucose metabolism improving insulin sensitivity via regulation of mitochondrial activities and inflammation …”

“…57 Further studies demonstrate that urolithin C also affects the triggering of intracellular signaling proteins influencing the β-cell function, especially the insulin secretion. 59 Urolithin A has also a valuable effect in the glucose metabolism improving insulin sensitivity via regulation of mitochondrial activities and inflammation. 60 Several papers have been recently reported about the antitumoral effect of urolithins.…”