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

Margherita Dall'Asta, Morgane Bayle, Jérémie Neasta, Guillaume Gautheron, Anne Virsolvy, Jean-François Quignard, Estelle Youl, Richard Magous, Jean-François Guichou, Alan Crozier, Daniele Del Rio, Gérard Cros, Catherine Oiry

Risultato della ricerca: Contributo in rivistaArticolo in rivista

6 Citazioni (Scopus)

Abstract

Background and PurposeThe 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 ApproachINS-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 ResultsAmong 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 Ca(v)1.2 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 ImplicationsUrolithin 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.
Lingua originaleEnglish
pagine (da-a)4065-4078
Numero di pagine14
RivistaBRITISH JOURNAL OF PHARMACOLOGY
Volume176
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Urolithin C
  • beta-cell function
  • polyphenols
  • type 2 diabetes

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