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

作者：Cigliola Valentina^*; Populaire Celine; Pierri Ciro L; Deutsch Samuel; Haefliger Jacques Antoine; Fadista Joao; Lyssenko Valeriya; Groop Leif; Rueedi Rico; Thorel Fabrizio; Herrera Pedro Luis; Meda Paolo^*

来源：PLos One, 2016, 11(3): e0150880.

DOI：10.1371/journal.pone.0150880

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing beta-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 beta-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 beta-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 beta-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex-and agematched 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 beta-cell function, presumably contributing to T2D pathogenesis.

• 出版日期2016-3-9