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A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Cigliola, Valentina; Populaire, Celine; Pierri, Ciro L; Deutsch, Samuel; Haefliger, Jacques-Antoine; Fadista, Joao LU ; Lyssenko, Valeriya LU ; Groop, Leif LU ; Rueedi, Rico and Thorel, Fabrizio, et al. (2016) In PLoS ONE 11(3).
Abstract
Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered... (More)
Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis. (Less)
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3
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Public Library of Science
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  • pmid:26959991
  • wos:000371992300083
  • scopus:84962532811
ISSN
1932-6203
DOI
10.1371/journal.pone.0150880
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English
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yes
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c8460af3-213e-40c9-bc2b-0408176cea35 (old id 8852838)
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http://www.ncbi.nlm.nih.gov/pubmed/26959991?dopt=Abstract
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2016-03-16 11:28:27
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@article{c8460af3-213e-40c9-bc2b-0408176cea35,
  abstract     = {Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis.},
  articleno    = {e0150880},
  author       = {Cigliola, Valentina and Populaire, Celine and Pierri, Ciro L and Deutsch, Samuel and Haefliger, Jacques-Antoine and Fadista, Joao and Lyssenko, Valeriya and Groop, Leif and Rueedi, Rico and Thorel, Fabrizio and Herrera, Pedro Luis and Meda, Paolo},
  issn         = {1932-6203},
  language     = {eng},
  number       = {3},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0150880},
  volume       = {11},
  year         = {2016},
}