TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass

Takamoto, Iseki; Kubota, Naoto; Nakaya, Keizo; Kumagai, Katsuyoshi; Hashimoto, Shinji; Kubota, Tetsuya; Inoue, Mariko; Kajiwara, Eiji; Katsuyama, Hisayuki; Obata, Atsushi; Sakurai, Yoshitaka; Iwamoto, Masahiko; Kitamura, Tadahiro; Ueki, Kohjiro; Kadowaki, Takashi

doi:10.1007/s00125-013-3131-6

Cited by 75 publications

(70 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, they reported no impaired effects on b-cell function in a b-cellspecific Tcf7l2 knockout mouse (23). This finding is in sharp contrast with previous reports showing reduced b-cell mass, a perturbed incretin response and GSIS with reduced insulin expression (24,27). Although there are no apparent explanations for these discrepant results they could reflect the application of B-cell-specific versus whole-islet knockdown strategies, as TCF7L2 is also expressed in a-cells (55), or a difference between inducible versus congenital knockdown of TCF7L2, as Wnt signaling is important for pancreas development (62).…”

contrasting

confidence: 56%

“…In support of a primary effect in pancreatic islets, the risk T-allele carriers show higher degree of open chromatin in pancreatic islets, but not in other tissues (22). Several mouse models of Tcf7l2 have been investigated (23)(24)(25)(26)(27)(28), but the diabetic phenotype has not been replicated in all studies. Experiments in rodent islets where TCF7L2 activity has been disrupted have usually demonstrated impaired GSIS (11,29,30).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TCF7L2 is a master regulator of insulin production and processing

Zhou

Park

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

contrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

TCF7L2 is a master regulator of insulin production and processing

Zhou

Park

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Moreover, the TCF7L2 gene is involved in modifying the expression of insulin and glucagon protein through Wnt signaling. A previous study has demonstrated a significant association between high expression of TCF7L2 in pancreatic beta cells and glucose metabolism (Takamoto et al, 2014). Zhou et al (2014) reported that the T allele of rs7903146, associated with diabetes risk, correlates with increased TCF7L2 expression and reduced insulin levels and secretion, thus the affected protein may regulate insulin production and the pathogenesis of type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 98%

Association between transcription factor 7-like 2 genetic polymorphisms and development of type 2 diabetes in a Chinese population

Jia

2016

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. We conducted a hospital-based case-control study to evaluate the relationship between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and type 2 diabetes mellitus risk in a Chinese population. Genotyping of TCF7L2 rs7903146 was carried out using the polymerase chain reaction-restriction fragment length polymorphism method. A chi-square test revealed a statistically significant difference between the distributions of rs7903146 genotypes in type 2 diabetes mellitus patient and control groups (chi-square = 10.49, P = 0.005). Using unconditional logistic regression analysis, we observed that the TT genotype of this polymorphism was significantly correlated with increased risk of developing type 2 diabetes mellitus compared to the CC genotype [odds ratio (OR) = 2.31, 95% confidence interval (CI) = 1.33-4.04]. Furthermore, we found that the rs7903146 sequence variation was also significantly associated with susceptibility to this disease under dominant (OR = 1.58, 95%CI = 1.09-2.28) and recessive models (OR = 2.11, 95%CI = 1.25-3.62). We conclude that the TCF7L2 rs7903146 genetic polymorphism is independently associated with the risk of developing type 2 diabetes mellitus under co-dominant, dominant, and recessive models.

show abstract

“…For example, TCF7L2 had no known role in T2D when intronic SNPs were first found to be associated with this disease. Subsequent expression and functional studies have now identified a key role for this gene in pancreatic beta-cell function [58][59].…”

Section: Association Does Not Imply Causalitymentioning

confidence: 99%

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Nair

Baier

2015

Rev Diabet Stud

View full text Add to dashboard Cite

■ AbstractGenetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking. Studies in isolated populations offer several advantages over outbred populations despite being, on average, much smaller in sample size. For example, reduced genetic variability, enrichment of rare variants, and a more uniform environment and lifestyle, which are hallmarks of isolated populations, can reduce the complexity of identifying disease-associated genes. To date, studies in isolated populations have provided valuable insight into the genetic basis of T2D by providing both a deeper understanding of previously identified T2D-associated variants (e.g. demonstrating that variants in KCNQ1 have a strong parent-of-origin effect) or providing novel variants (e.g. ABCC8 in Pima Indians, TBC1D4 in the Greenlandic population, HNF1A in Canadian Oji-Cree). This review summarizes advancements in genetic studies of T2D in outbred and isolated populations, and provides information on whether the difference in the prevalence of T2D in different populations (Pima Indians vs. non-Hispanic Whites and non-Hispanic Whites vs. non-Hispanic Blacks) can be explained by the difference in risk allele frequencies of established T2D variants.

show abstract

TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass

Abstract: TCF7L2 expressed in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass.

Cited by 75 publications

References 49 publications

TCF7L2 is a master regulator of insulin production and processing

TCF7L2 is a master regulator of insulin production and processing

Association between transcription factor 7-like 2 genetic polymorphisms and development of type 2 diabetes in a Chinese population

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Contact Info

Product

Resources

About