Year: 2014
Type: dissertation
Abstract: Transcription factor 7-like 2 (TCF7L2) is a principal downstream transcription factor that mediates the function of the developmental canonical Wnt signaling pathway. When partnered with -catenin, TCF7L2 stimulates Wnt target gene expression and mediates certain effects of other signaling cascades such as cAMP and insulin in cell type-specific manners. Recent genome-wide association studies have reproducibly revealed that common single nucleotide polymorphisms in TCF7L2 have the strongest genetic association with type 2 diabetes risk in a multitude of ethnic backgrounds. Following this hallmark discovery in 2006, the role of TCF7L2 in regulating metabolism and glucose homeostasis has been intensely investigated. Recent studies have shown that TCF7L2 regulates pancreatic -cell function and survival as well as the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1). As human carriers of TCF7L2 diabetes risk polymorphisms also exhibited increased hepatic glucose production, we aimed to determine the role of TCF7L2 in hepatic glucose metabolism. We revealed that hepatic TCF7L2 expression is regulated by nutrient availability as feeding increased TCF7L2 levels in mouse livers while insulin treatment stimulated TCF7L2 expression in hepatic cell lines. Treatment of hepatocytes with the Wnt ligand Wnt-3a decreased, while TCF7L2 knockdown increased gluconeogenic gene expression and glucose production, suggesting that TCF7L2 and Wnt signaling repress gluconeogenesis. To further examine the
Source: TSpace (University of Toronto)
Author: Wilfred Ip
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2729256283