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Br J Pharmacol. 2019 Aug 4. doi: 10.1111/bph.14821. [Epub ahead of print]

The Ellagitannin Metabolite Urolithin C is a Glucose-Dependent Regulator of Insulin Secretion through L-type Calcium Channel Activation.

Author information

1
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France.
2
Laboratoire de Pharmacologie, Faculté de Pharmacie, Univ Montpellier, Montpellier, France.
3
The Laboratory of Phytochemicals in Physiology, LS9 InterLab Group, Department of Food Science, University of Parma, Parma, Italy.
4
PhyMedExp, Univ Montpellier, CNRS, INSERM, Montpellier, France.
5
Université Bordeaux, INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Bordeaux, F-33000, France.
6
CBS, Univ Montpellier, CNRS, INSERM, Montpellier, France.
7
Department of Nutrition, University of California, Davis, CA, 95618, USA.
8
School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, G12 8QQ, UK.

Abstract

BACKGROUND AND PURPOSE:

The pharmacology of polyphenol metabolites on β-cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin-secreting function of β-cells and to explore the underlying mechanism.

EXPERIMENTAL APPROACH:

INS-1 β-cells, 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 β-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 β-cells. Our work paves the way for the design of polyphenol metabolite-inspired compounds aimed at ameliorating β-cell function.

KEYWORDS:

L-type Ca2+ channel; insulin secretion; polyphenol metabolite; urolithin C; β-cells

PMID:
31378934
DOI:
10.1111/bph.14821

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