Inheritance no doubt has a key role in predisposition of diabetes type 2 [10].Geneticist argued that genomics of T2D is explored well to understand and manage the pathogenesis of T2D [11]. These claims are premature according to others [12]; in fact, a few have doubt in contribution of genetic predisposition to T2D pathogenesis [13]. In Sixteenth century Peter Frank a physician from Montpellier for the every first time suggest that heredity is playing a role in diabetes [14]. The Frank’s view was supported by subsequent finding in 1950s and it was concluded that family history and genetics heterogeneity has a principal role in the predisposition of diabetes [15]. Earlier studies were mostly carried out on specific genes (i.e. those involved in glucose homeostasis) [16]. Considerable research by the end of 2005 was carried out throughout the world in spite of vast research only two genes polymorphism were found to be associated with type 2 diabetes: were E23K in KCNJ11 and P12A in PPARG [17][18]. Mutation in these genes causes monogenic diabetes [19][20]. In recent years genetics of diabetes type 2 is well explored due to advancement in molecular biology and also thanks to genome wide association study (GWAS) which facilitates the researcher in identifying various loci that is associated the diabetes [21][22]. Number of risk loci associated with diabetes type 2 is climbed up from just 3 identified in 2006 to more approximately 70 today, nevertheless up-to-date 90 genetic loci involved in the pathogenesis of T2D is identified by GWAS [23][24].

DECODE group of Iceland in the start of 2006 revealed the transcription factor-7– like 2 (TCF7L2) as an unexpected suspect gene for a diabetes type 2 [25]. After 2006 this gene drawn attention of geneticists and soon it was confirm that multiple polymorphisms in this gene has strong association with diabetes type 2 in multiple ethnic population. After the initial signals from DECODE group in Iceland widespread study is carried in white Europeans [26], Indians and Japanese [27–29], Mexican Americans [30], Chinese [31], and West Africans [32]. Studies in all racial population shows strong association of transcription factor-7– like 2 (TCF7L2) with diabetes type 2. Tracking of guilty genes nowadays is quite easy using new technologies. Due to technological advances, genetic variants in genes found guilty in diabetes can be assessed on a single chip. Recent advancement in genetic studies and genome wide association study has completely un-mask the complete genetic makeup of diabetes type 2 and identified number of variants in TCF7L2 associated with diabetes type 2, among other guilty genes it is the most promising gene in the development if type 2 diabetes [33–37].

TCF7L2 gene (Alternate names (1) T-cell-specific transcription factor 4, (2) HMG box transcription factor 4) encodes a protein, the Transcription factor 7-like 2 (T-cell specific) containing a transcription factor which has key role in blood glucose regulation in humans [38]. Cytogenetic location of this polymorphic gene is 10q25.2-q25.3 [39]. It contains 18 exons, 619 amino acids and exists in helix-turn-helix structure [40].Transcription factor 7-like 2 belongs to a family of transcription factors known as TCF/LEF family (containing TCF7 (TCF-1),TCF7L1 (TCF-3),TCF7L2 (TCF-4) and LEF1) these transcription factors binds to DNA via SOX-like high mobility group domain [41]. TCF/LEF family member specifically TCF7L2 regulate WNT pathway which has critical role in embryonic development of pancreas and islets, cell proliferation, Causation of several cancers, Regulation of adiposeness, and release of glucagon-like peptide-1 (GLP-1) from intestinal endocrine L-cells which effect two things mainly first it effect insulin secretion secondly the generation of new β stem cells from the ductal precursor cells and hence has critical role in controlling glucose homeostasis [42][43]. The TCF7L2 is distributed and expressed in brain, pancreas, liver, intestine and fat cells [44].

Grant et.al and saxena et.al in 2006 for the first time correlate polymorphism in TCF7L2 with type 2 diabetes. Before that Pub-Med software was search for keyword TCF7L2 reveals 218 articles but none of that shared the term “diabetes” means the grant et al (2006) and saxena et.al (2006) are the pioneer in correlating TCF7L2 polymorphism with incidence of diabetes type 2. After that TCF7L2 replication studies were carried out word wide in different ethnic population each study conforming strong association of TCF7L2 with type 2 diabetes [45]. A comprehensive list of studies on Type 2 Diabetes Susceptibility Gene TCF7L2 rite from 2006, year of its discovery to 2019 is enlisted in the table 1.

Genome-wide association studies are well-powered, systemic, organized and comprehensive survey to explore and identify the link of various genetic variation (SNPs) and disease predisposition on large genomic scale [46]. Genome wide association studies as laid down spectacular advances in finding genetic cause of the diseases like cancer, diabetes, kidney failure, depression, asthma and many more. Promising Genome wide association studies also found TCF7L2 gene culprit in diabetes Type 2 [47]. In earlier genetic study era (start of 2007), two stage genome wide associations was conducted to identify different risk loci in TCF7L2. At stage first a meta analysis was conducted in 2367 French patients a consent form was signed from all patients and studied was approved by ethics committee of French general health hospital and Imperial College London, the study results show strong association of TCF7L2 with diabetes type 2 [48]. Second stage (late in year 2007) a huge genomic study was conducted in UK white population. In this study geneticist included a new parameter of association of TCF7L2 with diabetes type 1 as some geneticist in that time predict that type 1 diabetes is nothing but severe case of type 2 diabetes. All identified SNPs of TCF7L2 in this study shows strong association with type 2 diabetes but no association with type 1 diabetes confirming type 1diabetes as an autoimmune disease [49]. Later further genome wide association studies carried out in different ethnic population stamped TCF7L2 as a guilty gene in type 2 diabetes [50, 51].

The Wnt signaling pathways is greatly important in regulating carcinogenesis and embryonic development (stem cell differentiation, amplification and migration) also involved in the development of the body parts [52][53]. Wnt signaling pathway (the canonical pathway or beta-catenin/TCF7L2-dependent pathway) is expressed in liver, pancreas, brain and adipose tissues [54]. In pancreas it helps in the development of pancreas, islet function, insulin production and secretion. In beta cells of pancreas canonical wnt signaling is modulated by two hormones namely glucoincretin hormone glucagon-like peptide-1 and the chemokine stromal cell-derived factor-1, furthermore glucagon-like peptide-1and its agonist exendin-4 restore the pancreatic beta cells mass by switching on Wnt signaling which then start proliferation to restore mass of beta cell [55]. Genome-wide association studies (GWAS) have identified several risk variants in TCF7L2 that is found culprit in type 2 diabetes. Interestingly most of these risk variants encode proteins that are involved in islet growth and functioning. Seven of them are part of genes that regulate Wnt signaling. Thus canonical Wnt signaling and beta-cell function is greatly influenced by TCF7L2 mutation. Polymorphism in TCF7L2 leads to loss in function of pancreas; impair insulin secretion, perturbations in the Wnt signaling pathway that leads to type 2 diabetes [56][57].

Candidate gene association studies (CGAS) and genome wide association studies (GWAS) identified multiple genes associated with diabetes type 2, transcription factor 7-like 2 (TCF7L2) is gang head of type 2 diabetes susceptible genes [58]. Risk variants leads to over-expression of TCF7L2 gene in beta cells of pancreas but the mechanism is not fully understood and it is a question which is still need to be answered by geneticists, resulting in reducing secretion of insulin from beta cells and hence increasing blood sugar level [59][60]. Comprehensive knowledge about TCF7L2 have significant role in controlling diabetes, separating and identifying the prospective diabetes individuals with high risk diabetes associated loci in a population so that preventive measures can be initiated [61][62].

Funding. None.

Conflict of interest. None.

Author Contribution. Asif Jan contributed in literature search, finalizing topic, write-up, giving final shape to this review paper and submission of paper. Humerah Jan and Zaki Ullah helped in writing the manuscript.

Acknowledgement. This review paper was supported by Dr Hamayun. We are thankful for his moderation throughout the paper. We are also thankful to Dr Sidra who helped us for writing manuscript.