Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

Approximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (=TCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study (GWAS). As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups, great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas, liver and adipose tissues. Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis, studies conducted to date have also generated controversial suggestions. Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies. I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk, a gain-of-function event versus a loss-of-function event. This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives.