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 genotype-dependent 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.

Circulating microRNAs as diagnostic biomarkers for pancreatic cancer

“…Another predicted target is TCF7L2, whose polymorphisms have been correlated to type 2 diabetes mellitus (T2DM). [31] Functional down-regulation of this protein via miR-938 could induce dysregulation of glucose homeostasis. Similarly, dysregulation of circulating miR-126-3p has been reported as a marker for impaired glucose intolerance and new-onset T2DM.…”

Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes

“…Having established that CART affects expression of insulin and genes crucial for insulin secretion and processing, we next examined expression of the transcription factors known to regulate these genes (Melloul et al, 2002;Zhou et al, 2014;Fu et al, 2013). CART KD resulted in decreased expression of Tcf7l2, Mafa, Isl-1, Pdx-1, NeuroD1, Nkx2.2 and Nkx6.1 mRNA to 51.4 ± 3.7%, 39 ± 7.9%, 50.5 ± 4.3%, 61.7 ± 2.5%, 56.9 ± 5.9%, 65.1 ± 4.8%, and 79.7 ± 6.5% respectively (p < 0.001 and p < 0.05 for Nkx6.1, Fig.…”

“…Furthermore, it was recently shown that TCF7L2, through binding to ISL-1, regulates proinsulin production and processing via e.g. MAFA, PDX-1 and PCSK2 (Zhou et al, 2014).…”

Tcf7l2 Gene Polymorphism in T2dm with Patients in Turkish Population

“…However, a previous study [19] has shown that TCF7L2 has 17 exons, of which five are alternative splicing. Genetic variants of gene are associated with increased risk of Type 2 Diabetes [20,21]. The prevalence of Type 2 Diabetes shows wide ethnic and geographic variations.…”