The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective

Ip, Wilfred; Chiang, Yu-Ting; Jin, Tianru

doi:10.1186/2045-3701-2-28

Cited by 98 publications

(93 citation statements)

References 101 publications

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“…(3) showing that TCF7L2 variants were strongly associated with T2DM risk, several other studies consistently replicated this association in different ethnicities [reviewed in (4)]. Among the TCF7L2 variants, the rs7903146 (C/T) SNP seems to have the more robust effect in Caucasian populations (4,9). Here, we successfully replicated the association between the TCF7L2 rs7903146 SNP and risk for T2DM in Caucasian-Brazilian subjects from Southern of Brazil, probably under an additive inheritance model given that the risk conferred by the T/T genotype was higher than that conferred by heterozygous genotype.…”

Section: Discussionmentioning

confidence: 92%

“…Up to now, all of these studies firmly establish TCF7L2 gene as the strongest genetic risk factor for T2DM (4)(5)(6)(7)(8). Amongst the TCF7L2 variants, two intronic SNPs (rs12255372 and rs7903146) are the most closely associated with T2DM, and although both have showed a significant linkage disequilibrium (LD), the rs7903146 (C/T) variant seems to have the strongest effect in Caucasian populations (4,9).…”

Section: Introductionmentioning

confidence: 95%

“…TCF7L2 forms heterodimers with b-catenin, inducing the expression of various genes, including the insulinotropic hormone glucagon-like peptide 1 (GLP-1) gene, the insulin gene, and other genes that encode proteins involved in processing and exocytose of insulin granules (9,(11)(12)(13). As GLP-1 and insulin play a key role in blood glucose homeostasis, it was hypothesized that TCF7L2 variants may modify T2DM susceptibility by indirectly reducing GLP-1 secretion from enteroendocrine cells (14).…”

Section: Introductionmentioning

confidence: 99%

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The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

Assmann

Duarte

Rheinheimer

et al. 2014

Arq Bras Endocrinol Metab

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The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil O polimorfismo rs7903146 (C/T) no gene TCF7L2 está associado com risco para o diabetes melito tipo 2 em uma população do sul do BrasilTaís S. Assmann 1,2 , Guilherme C. K. Duarte 1 , Jakeline Rheinheimer 1,2 , Lavínia A. Cruz 1 , Luís H. Canani 1,2 , Daisy Crispim 1,2 ABSTRACTObjective: The aim of this study was to investigate the association between the rs7903146 (C/T) polymorphism in the TCF7L2 gene and type 2 diabetes mellitus, in a Southern-Brazilian population. Materials and methods: The TCF7L2 rs7903146 polymorphism was genotyped in 953 type 2 diabetic patients and 535 non-diabetic subjects. All subjects were white. The polymorphism was genotyped by Real-Time PCR using TaqMan MGB probes (Life Technologies). Odds ratios (OR) and 95% confidence intervals (CI) were calculated for additive, recessive and dominant inheritance models. Results: Genotype and allele frequencies of the rs7903146 polymorphism differed significantly between type 2 diabetic patients and non-diabetic subjects (P = 0.001 and P = 0.0001, respectively). The frequency of the minor allele was 38% in type 2 diabetes group and 31% in non--diabetic subjects, and this allele was significantly associated with type 2 diabetes risk (OR = 1.42, 95% CI 1.15 -1.76 for the dominant model of inheritance). Moreover, the T/T genotype was associated with a higher risk for type 2 diabetes (OR = 1.83, 95% CI 1.3-2.5) than the presence of only one copy of the T allele (OR = 1.31, 95% CI 1.1-1.6). Both results were adjusted for age and gender. Conclusions: Our results confirm the association between the TCF7L2 rs7903146 polymorphism and increase risk for type 2 diabetes in Southern-Brazil. Arq Bras Endocrinol Metab. 2014;58(9):918-25 Keywords Single nucleotide polymorphism; type 2 diabetes mellitus; transcription factor 7-like 2 (TCF7L2) RESUMO Objetivo: O objetivo deste estudo foi investigar a associação entre o polimorfismo rs7903146 (C/T) no gene TCF7L2 e o diabetes melito tipo 2 em uma população do sul do Brasil. Materiais e méto-dos: O polimorfismo rs7903146 (C/T) no gene TCF7L2 foi genotipado em 953 pacientes com diabetes melito tipo 2 e em 535 indivíduos não diabéticos. Todos os indivíduos estudados eram brancos. O polimorfismo foi genotipado por meio da técnica de PCR em tempo real, utilizando sondas TaqMan MGB (Life Technologies). A razão de chances e o intervalo de confiança de 95% foram calculados para os modelos de herança: aditivo, recessivo e dominante. Resultados: As frequências genotípicas e alélicas do polimorfismo rs7903146 diferiram significativamente entre os pacientes com diabetes melito tipo 2 e indivíduos não diabéticos (P = 0,001 e P = 0,0001, respectivamente). A frequência do menor alelo foi 38% no grupo dos pacientes com diabetes melito tipo 2 e 31% no grupo dos indivíduos não diabéticos, sendo esse alelo significativamente associado com risco para o diabetes melito tipo 2 (RC = 1,42; IC 95% 1,15 -1,76 para o modelo de heranç...

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

Assmann

Duarte

Rheinheimer

et al. 2014

Arq Bras Endocrinol Metab

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“…10 In exploring mechanisms underlying GLP-1 function, a few recent studies have demonstrated that the Wnt signaling pathway effector cat/TCF, a complex formed by free β-catenin (β-cat) and a member of the T-cell factor (TCF) family, regulates not only gut gcg mRNA transcription and GLP-1 production, but also GLP-1 function in pancreatic β-cells and brain neuronal cells. [11][12][13] Here we present our current knowledge on GLP-1 and its "degradation" products, and summarize our current understanding on the metabolic, proliferative and protective effects of GLP-1. We mainly focus on GLP-1 Downloaded by [Stony Brook University] at 06: 46 29 June 2015 termed as glucose competence.…”

Section: Introductionmentioning

confidence: 99%

New insight into the mechanisms underlying the function of the incretin hormone glucagon-like peptide-1 in pancreatic β-cells

Xiong

Shao

Jin

2012

Islets

Self Cite

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During the past two decades, the exploration of function of two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), has led to the development of two categories of novel therapeutic agents for diabetes and its complications, known as GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors. Mechanisms underlying the function of GLP-1, however, still need to be further explored. GLP-1 not only functions as an incretin hormone in stimulating insulin secretion in response to nutritional, hormonal and neuronal stimulations, but also acts as an "insulin-like" factor in β-cell and extra-pancreatic organs. In addition to these insulinotropic and insulinomimetic effects, GLP-1 was shown to exert its protective effect in β-cell by repressing the expression of TxNIP, a mediator of glucolipotoxicity. A number of recent studies have shown that the Wnt signaling pathway effector, the bipartite transcription factor β-catenin/TCF, controls not only the production of GLP-1, but also the function of GLP-1. Furthermore, previously assumed "degradation" products of GLP-1(7-36)amide, including GLP-1(9-36)amide and GLP-1(28-36)amide, have been shown to exert beneficial effect in pancreas and extra-pancreatic tissues or cell lineages. Here we summarized our current knowledge on the metabolic, proliferative and protective effects of GLP-1(7-36)amide and its cleavage fragments, mainly focusing on pancreatic β-cells and the involvement of the Wnt signaling pathway effector β-catenin.

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“…The TCF7L2 gene is located on chromosome 10q25.3 and has been identified as a major T2DM susceptibility gene by a large scale genome-wide association study (GWAS) in 2006 (Grant et al, 2006). This important finding has been subsequently validated by genetic analyses of disease susceptibility in various ethnic groups in recent years (Ip et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Association of TCF7L2 gene polymorphisms with susceptibility to type 2 diabetes mellitus in a Chinese Hui population

Yang¹,

Yj²,

Liu³

2015

Genet. Mol. Res.

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ABSTRACT. Diabetes is one of costly chronic diseases. Previous studies across several ethnicities have shown that polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene were strongly associated with susceptibility to type 2 diabetes (T2DM). In the present study, the association between the TCF7L2 gene and the susceptibility to T2DM in a Chinese Hui population was interrogated. Polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis and allelic specific PCR were employed for examining the TCF7L2 gene rs12255372 (G>T) and rs290487 (C>T), and rs7901695 (T>C) polymorphisms, respectively, in 109 healthy individuals and 111 subjects with T2DM who were of Chinese Hui descent and lived in the Ningxia Hui Autonomous Region of China. The results showed that the genotypic frequency of rs290487 and the allelic frequency distributions of the rs7901695 and rs290487 loci were not significantly different between patients and controls in this population. However, both the genotypic and the allelic frequencies at rs12255372 exhibited statistical 10065 TCF7L2 gene polymorphisms and T2DM©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 10064-10071 (2015) differences between the patients with T2DM and the unaffected cohort (P < 0.01). In addition, the frequency of the G allele at the rs12255372 locus in the patients was higher than that in healthy individuals (OR = 1.198, 95%CI = 1.097-1.307). These findings suggest that the TCF7L2 rs12255372 (G>T) polymorphism might be one of the most important genetic factors associated with T2DM susceptibility, and that individuals in the Chinese Hui population who carry a G allele at this locus might be at risk to develop T2DM.

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The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective

Cited by 98 publications

References 101 publications

The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

New insight into the mechanisms underlying the function of the incretin hormone glucagon-like peptide-1 in pancreatic β-cells

Association of TCF7L2 gene polymorphisms with susceptibility to type 2 diabetes mellitus in a Chinese Hui population

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