Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

<h4>Background/aims</h4>Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.<h4>Methods</h4>We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice,...

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Autores principales:	David Vallois, Guy Niederhäuser, Mark Ibberson, Vini Nagaraj, Lorella Marselli, Piero Marchetti, Jean-Yves Chatton, Bernard Thorens
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/382879c998524f93a5a8dc3fe0323595
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spelling	oai:doaj.org-article:382879c998524f93a5a8dc3fe03235952021-11-25T06:07:12ZGluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.1932-620310.1371/journal.pone.0103277https://doaj.org/article/382879c998524f93a5a8dc3fe03235952014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25058609/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background/aims</h4>Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.<h4>Methods</h4>We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed.<h4>Results</h4>Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation.<h4>Conclusions/interpretation</h4>Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.David ValloisGuy NiederhäuserMark IbbersonVini NagarajLorella MarselliPiero MarchettiJean-Yves ChattonBernard ThorensPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e103277 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Vallois Guy Niederhäuser Mark Ibberson Vini Nagaraj Lorella Marselli Piero Marchetti Jean-Yves Chatton Bernard Thorens Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
description	<h4>Background/aims</h4>Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.<h4>Methods</h4>We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed.<h4>Results</h4>Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation.<h4>Conclusions/interpretation</h4>Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.
format	article
author	David Vallois Guy Niederhäuser Mark Ibberson Vini Nagaraj Lorella Marselli Piero Marchetti Jean-Yves Chatton Bernard Thorens
author_facet	David Vallois Guy Niederhäuser Mark Ibberson Vini Nagaraj Lorella Marselli Piero Marchetti Jean-Yves Chatton Bernard Thorens
author_sort	David Vallois
title	Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
title_short	Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
title_full	Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
title_fullStr	Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
title_full_unstemmed	Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.
title_sort	gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of fxyd3 expression.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/382879c998524f93a5a8dc3fe0323595
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Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

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