TCF7L2, short for Transcription Factor 7 Like 2, is a transcription factor that is a fundamental part of the Wnt signaling pathway. It has highly conserved sequence regions corresponding to functional domains. TCF7L2 is of great biological importance as it is strongly associated with type 2 diabetes (T2D), being the most potent locus for T2D risk, and is also linked to other diseases, highlighting its role in various biological processes [1,4].

In T2D, TCF7L2 variants associated with risk influence the initial therapeutic success of sulfonylurea. Observational and meal test trials suggest that TCF7L2 modifies the association between diet and insulin resistance in non-diabetes participants. Some randomized controlled trials show mixed results regarding its impact on glycemic parameters in response to dietary interventions. In gastric cancer, TCF7L2 is highly expressed, promotes anoikis resistance and metastasis by transcriptionally activating PLAUR, and is an independent risk factor for poor prognosis [1,2,3]. In adipose progenitor biology, TCF7L2 plays a complex role with dose-and depot-dependent effects on adipogenesis, potentially influencing T2D risk [5]. In Asian Indians, the TCF7L2 gene is associated with postprandial triglyceride dysmetabolism, a novel mechanism for diabetes risk [6].

In conclusion, TCF7L2 is a key transcription factor in the Wnt signaling pathway. Its functions are diverse, significantly influencing the development of type 2 diabetes, gastric cancer, and other conditions. Studies, though not always involving KO/CKO mouse models, have provided insights into how TCF7L2 contributes to disease-related biological processes such as insulin resistance, cancer metastasis, and lipid metabolism, which may aid in developing targeted therapies and understanding disease mechanisms.

References:

1. Del Bosque-Plata, Laura, Martínez-Martínez, Eduardo, Espinoza-Camacho, Miguel Ángel, Gragnoli, Claudia. 2021. The Role of TCF7L2 in Type 2 Diabetes. In Diabetes, 70, 1220-1228. doi:10.2337/db20-0573. https://pubmed.ncbi.nlm.nih.gov/34016596/

2. Zhang, Tao, Wang, Bofang, Su, Fei, Li, Xue-Mei, Chen, Hao. 2022. TCF7L2 promotes anoikis resistance and metastasis of gastric cancer by transcriptionally activating PLAUR. In International journal of biological sciences, 18, 4560-4577. doi:10.7150/ijbs.69933. https://pubmed.ncbi.nlm.nih.gov/35864968/

3. Hosseinpour-Niazi, Somayeh, Mirmiran, Parvin, Hosseini, Shabnam, Daneshpour, Maryam S, Azizi, Fereidoun. 2022. Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review. In Nutrition journal, 21, 59. doi:10.1186/s12937-022-00813-w. https://pubmed.ncbi.nlm.nih.gov/36155628/

4. Del Bosque-Plata, Laura, Hernández-Cortés, Eduardo Pavel, Gragnoli, Claudia. 2021. The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes. In Journal of cellular physiology, 237, 301-312. doi:10.1002/jcp.30581. https://pubmed.ncbi.nlm.nih.gov/34612510/

5. Verma, Manu, Loh, Nellie Y, Sabaratnam, Rugivan, Karpe, Fredrik, Christodoulides, Constantinos. 2022. TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes. In Metabolism: clinical and experimental, 133, 155240. doi:10.1016/j.metabol.2022.155240. https://pubmed.ncbi.nlm.nih.gov/35697299/

6. Madhu, Sri Venkata, Mishra, Brijesh Kumar, Mannar, Velmurugan, Banerjee, Basudev, Agrawal, Vivek. 2022. TCF7L2 gene associated postprandial triglyceride dysmetabolism- a novel mechanism for diabetes risk among Asian Indians. In Frontiers in endocrinology, 13, 973718. doi:10.3389/fendo.2022.973718. https://pubmed.ncbi.nlm.nih.gov/36263318/