The Role of <i>TCF7L2</i> in Type 2 Diabetes

Bosque-Plata, Laura del; Martínez‐Martínez, Eduardo; Espinoza-Camacho, Miguel Ángel; Gragnoli, Claudia

doi:10.2337/db20-0573

Cited by 67 publications

(49 citation statements)

References 49 publications

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“…The association of TCF7L2 with T2D is one of the most powerful genetically discoveries in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins (Del Bosque‐Plata et al, 2021 ). TCF7L2 and other proteins of the Wnt network have been related to various human disorders, reflecting their role in their pathogenesis (Lucero et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes

Bosque-Plata

Hernández-Cortés

Gragnoli

2021

Journal Cellular Physiology

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The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, regulating gene expression. It was initially identified in cancer research and embryologic developmental studies. Later, the TCF7L2 gene was linked to type 2 diabetes (T2D), implicating TCF7L2 and Wnt-signaling in metabolic disorders and homeostasis. In fact, TCF7L2-T2D variants confer the greatest relative risk for T2D, unquestionably predicting conversion to T2D in individuals with impaired glucose tolerance. We aim to describe the relevance of TCF7L2 in other human disorders. The TCF7L2-single nucleotide polymorphisms (SNPs) and T2D-risk association have been replicated in numerous follow-up studies, and research has now been performed in several other diseases. In this article, we discuss common TCF7L2-T2D variants within the framework of their association with human diseases. The TCF7L2 functional regions need to be further investigated because the molecular and cellular mechanisms through which TCF7L2 contributes to risk associations with different diseases are still not fully elucidated. In this review, we show the association of common TCF7L2-T2D variants with many types of diseases. However, the role of rare genetic variations in the TCF7L2 gene in distinct diseases and ethnic groups has not been explored, and understanding their impact on specific phenotypes will be of clinical relevance. This offers an excellent opportunity to gain a clearer picture of the role that the TCF7L2 gene plays in the pathophysiology of human diseases. The potential pleiotropic role of TCF7L2 may underlie a possible pathway for comorbidity in human disorders.

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Section: Introductionmentioning

confidence: 99%

The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes

Bosque-Plata

Hernández-Cortés

Gragnoli

2021

Journal Cellular Physiology

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“…We observe downregulation of WNT3A , WNT5A , and WNT10B which is consistent with observation of enhanced TCF/LEF gene expression which represses target gene expression when Wnt signals are absent ( 42 ). Wnt effectors such as TCF7L2 may be potential targets for therapeutic treatment of Wnt-related metabolic disease ( 43 ). TCF7L2 mRNA expression is reported to be the strongest type-2 diabetes candidate gene and inactivation of TCF7L2 leads to hepatic insulin resistance and decreased whole body glucose tolerance ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…Wnt effectors such as TCF7L2 may be potential targets for therapeutic treatment of Wnt-related metabolic disease ( 43 ). TCF7L2 mRNA expression is reported to be the strongest type-2 diabetes candidate gene and inactivation of TCF7L2 leads to hepatic insulin resistance and decreased whole body glucose tolerance ( 43 ). In the current study, conversely, TCF7L2 mRNA expression was negatively correlated with HOMA2-IR scores (ρ = -0.526, P = 0.017, data not shown).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Subcutaneous White Adipose Tissue Inflammatory Environment Modelling in Non-Insulin Resistant Obesity and Responses to Omega-3 Fatty Acids – A Double Blind, Randomised Clinical Trial

et al. 2022

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BackgroundObesity is associated with enhanced lipid accumulation and the expansion of adipose tissue accompanied by hypoxia and inflammatory signalling. Investigation in human subcutaneous white adipose tissue (scWAT) in people living with obesity in which metabolic complications such as insulin resistance are yet to manifest is limited, and the mechanisms by which these processes are dysregulated are not well elucidated. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have been shown to modulate the expression of genes associated with lipid accumulation and collagen deposition and reduce the number of inflammatory macrophages in adipose tissue from individuals with insulin resistance. Therefore, these lipids may have positive actions on obesity associated scWAT hypertrophy and inflammation.MethodsTo evaluate obesity-associated tissue remodelling and responses to LC n-3 PUFAs, abdominal scWAT biopsies were collected from normal weight individuals and those living with obesity prior to and following 12-week intervention with marine LC n-3 PUFAs (1.1 g EPA + 0.8 g DHA daily). RNA sequencing, qRT-PCR, and histochemical staining were used to assess remodelling- and inflammatory-associated gene expression, tissue morphology and macrophage infiltration.ResultsObesity was associated with scWAT hypertrophy (P < 0.001), hypoxia, remodelling, and inflammatory macrophage infiltration (P = 0.023). Furthermore, we highlight the novel dysregulation of Wnt signalling in scWAT in non-insulin resistant obesity. LC n-3 PUFAs beneficially modulated the scWAT environment through downregulating the expression of genes associated with inflammatory and remodelling pathways (P <0.001), but there were altered outcomes in individuals living with obesity in comparison to normal weight individuals.ConclusionOur data identify dysregulation of Wnt signalling, hypoxia, and hypertrophy, and enhanced macrophage infiltration in scWAT in non-insulin resistant obesity. LC n-3 PUFAs modulate some of these processes, especially in normal weight individuals which may be preventative and limit the development of restrictive and inflammatory scWAT in the development of obesity. We conclude that a higher dose or longer duration of LC n-3 PUFA intervention may be needed to reduce obesity-associated scWAT inflammation and promote tissue homeostasis.Clinical Trial Registrationwww.isrctn.com, identifier ISRCTN96712688.

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“…H-Ras–expressing UB cells had a high ability to migrate forming long unbranched tubules, whereas TC21-expressing UB cells were characterized with branching excessively with a reduced capacity to migrate ( 29 ). Additionally, the diabetes gene and Wnt pathway effector TCF7L2 may increase susceptibility to both diabetes and kidney disease ( 30 ). Hence, the differentially methylated mRNAs provide the clues for understanding the distinct pathogenesis of uropathy.…”

Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy

et al. 2022

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BackgroundCongenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N6-methyladenosine (m6A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m6A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m6A methylation in CAKUT.MethodsUsing m6A-mRNA epitranscriptomic microarray, we investigated the m6A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group).ResultsA total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m6A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m6A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m6A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison.ConclusionThe current results highlight the pathogenesis of m6A methylation in obstructive and reflux uropathy.

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The Role of TCF7L2 in Type 2 Diabetes

Cited by 67 publications

References 49 publications

The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes

The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes

Dysregulation of Subcutaneous White Adipose Tissue Inflammatory Environment Modelling in Non-Insulin Resistant Obesity and Responses to Omega-3 Fatty Acids – A Double Blind, Randomised Clinical Trial

N6-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy

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