TCF7L2 is a master regulator of insulin production and processing

Abstract

Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotypedependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

“…Of note, Tcf7l2 silencing in INS1 beta cells lowers the expression of Ca 2? channel subunits [141], suggesting that TCF7L2 may exert control, either directly or indirectly, over the Ca 2? -signaling machinery.…”

MIRNAS: Early Prognostic Biomarkers for Type 2 Diabetes Mellitus?

“…However, for complex traits like diabetes, where lifestyle, environmental factors and genetic factors play a major role in the development of disease, prediction of risk on the basis of genetic variants has been limited to a factor of not more than 0.6 [17]. More than 50 genome-wide association analysis have been performed in different populations and more than 60 loci have been identified to be associated/linked with T2DM [18].…”

“…We would, however, like to discuss about a few important genetic loci that have shown association with T2DM. Several GWAS studies have revealed that variants in TCF7L2 gene confer the strongest risk of T2DM [18,22,23]. The risk-associated polymorphisms of TCF7L2 regulate the expression of certain transcripts and thus are physiologically significant.…”

“…The risk-associated polymorphisms of TCF7L2 regulate the expression of certain transcripts and thus are physiologically significant. TCF7L2 plays a major role in Wnt signaling and thus is thought to be associated with β-cell proliferation and maintenance [24]; and also regulates the genes involved in insulin exocytosis [18]. A single nucleotide polymorphism (SNP) at 13q13.1 (rs1359790) also showed high risk for T2DM and the closest gene to it, SPRY2, is involved in growth and development of pancreas via MAPK pathway [25].…”

Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

“…TCF7L2 encodes a transcription factor and is considered a master regulator of a number of genes involved in insulin production and processing (Zhou, Park et al 2014). The T risk allele of TCF7L2 is located more in open chromatin, in contrast to the C non-risk allele, and has shown greater enhancer activity, suggesting that accessibility of transcription factors to the DNA may be influenced by genetic variants (Gaulton, Nammo et al 2010).…”