The ellagitannin metabolite urolithin C is a glucose-dependent regulator of insulin secretion through activation of L-type calcium channels

Background and Purpose The pharmacology of polyphenol metabolites on beta‐cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin‐secreting function of beta‐cells and to explore the underlying mechanisms. Experimental Approach INS‐1 beta‐cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole‐cell patch‐clamp recordings were used for mechanistic studies. Key Results Among a set of polyphenol metabolites, we found that exposure of INS‐1 beta‐cells to urolithins A and C enhanced glucose‐stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose‐dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non‐stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav1.2 L‐type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization‐induced increase in intracellular Ca2+ in INS‐1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose‐dependently enhanced the L‐type Ca2+ current for levels of depolarization above threshold and shifted its voltage‐dependent activation towards more negative potentials in INS‐1 cells. Conclusion and Implications Urolithin C is a glucose‐dependent activator of insulin secretion acting by facilitating L‐type Ca2+ channel opening and Ca2+ influx into pancreatic beta‐cells. Our work paves the way for the design of polyphenol metabolite‐inspired compounds aimed at ameliorating beta‐cell function.