English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Pro

Presents the zaia usage as premium feature

ZAIA

Presents AI Discovery search usage as a premium feature

AI Discovery

Presents AI Discovery explain and summary usage as a premium feature

Content Analysis

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Presents the pdf analysis as premium feature

PDF Analysis

1500 Top-up

3000 Top-up

Zendy Basic

2500 Top-up

Zendy Unlimited

Presents the access of premium content as premium feature

Premium Content

The transcription factor  T-cell factor 7-like 2  ( TCF7L2 ) confers type 2 diabetes risk mainly through impaired insulin secretion, perturbed incretin effect and reduced beta-cell survival. The aim of this study was to identify the molecular mechanism through which TCF7L2 influences beta-cell survival. TCF7L2 target genes in INS-1 cells were identified using Chromatin Immunoprecipitation. Validation of targets was obtained by: siRNA silencing, real-time quantitative polymerase chain reaction, electrophoretic mobility shift assay, luciferase reporter assays and western blot. Apoptosis rate was measured by DNA degradation and caspase-3 content. Islet viability was estimated by measuring metabolic rate. TCF7L2 binds to 3646 gene promoters in INS-1 cells in high or low glucose, including  Tp53, Pten, Uggt1, Adamts9  and  Fto . SiRNA-mediated reduction in TCF7L2 activity resulted in increased apoptosis and increased expression of  Tp53 , which resulted in elevated p53 protein activity and an increased expression of the p53 target gene  Tp53inp1  (encoding p53-induced-nuclear-protein 1). Reversing the increase in p53INP1 protein expression, seen after  Tcf7l2  silencing, protected INS-1 cells from  Tcf7l2  depletion-induced apoptosis. This result was replicated in primary rat islets. The risk T-allele of rs7903146 is associated with increased  TCF7L2  mRNA expression and transcriptional activity. On the other hand,  in vitro  silencing of  TCF7L2  lead to increased apoptosis. One possibility is that the risk T-allele increases expression of an inhibitory TCF7L2 isoform with lower transcriptional activity. These results identify the p53-p53INP1 pathway as a molecular mechanism through which TCF7L2 may affect beta-cell survival and established a molecular link between  Tcf7l2  and two type 2 diabetes-associated genes,  Tp53inp1  and  Adamts9 .

Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway