Type 2 Diabetes Mellitus and TCF7L2

Updated: Dec 14, 2018
  • Author: Ali Torkamani, PhD; Chief Editor: Keith K Vaux, MD  more...
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Practice Essentials

Transcription factor 7–like 2 (TCF7L2) variants have been associated with type 2 diabetes mellitus in multiple ethnic groups. [1, 2, 3, 4, 5, 6, 7] Specific associated variants increase the risk of type 2 diabetes 1.5-fold in heterozygotes and 2.4-fold in homozygotes, corresponding to a population attributable risk of 21%. This makes TCF7L2 variants the strongest known genetic risk factors for type 2 diabetes. [8, 9]

TCF7L2 was discovered as a type 2 diabetes susceptibility gene after a strong linkage signal was mapped to chromosome 10q in a Mexican-American population. This region was later fine-mapped in the Icelandic population and confirmed in United States and Danish cohorts, where the risk locus was found to be located in intron 3 of the TCF7L2 gene. There are indications that this gene may play a role in cancer as well as in diabetes. [10]  Subsequent studies have shown that several noncoding genetic variants of TCF7L2 are associated with type 2 diabetes risk in populations of diverse ancestries in the United Kingdom, the Netherlands, Finland, Sweden, France, India, and Japan. [11]

The TCF7L2 gene is polymorphic, and a number of loci have been identified, such as the rs10749127, rs10787475, rs11196224, rs12775879, rs17130188, rs290481, rs290487, rs290489, rs3750804, rs4918792, rs6585194, rs7085532, rs7094463, rs7919409, rs966227, rs7903146, rs11196205, and rs12255372 polymorphisms. Among these single nucleotide polymorphisms (SNPs), the TCF7L2 rs7903146 (intron 4) shows the strongest association with type 2 diabetes. [12]  

The incidence of type 2 diabetes in African American women is more than twice that of white women in the United States. However, while more than 75 genetic loci for type 2 diabetes have been discovered in European, Asian, and Mexican ancestry populations, only 3 novel variants have been discovered in genome-wide association studies (GWAS) of African ancestry (AA) populations; most notable is SNP TCF7L2 rs7903146, the variant most significantly associated with type 2 diabetes to date. [13]

TCF7L2 is a transcription factor and key component of the Wnt signaling pathway, and it is involved in the development of a wide variety of cell lineages and organs. [14] Potential mechanisms through which TCF7L2 variants influence type 2 diabetes include its role in adipogenesis, myogenesis, and pancreatic islet development, as well as in beta-cell survival and insulin secretory granule function. [15, 16] TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. [17] It is also involved in the transcriptional regulation of the genes for proglucagon and the glucagon-like peptides GLP-1 and GLP-2; these peptides play a role in postprandial insulin secretion. [18]

Finally, TCF7L2 polymorphisms have been associated with impaired insulin secretion, glucose production, and glucose tolerance via direct effects on pancreatic islet beta cells. [19, 20] Indeed, dysregulation of glucose metabolism, decreased processing of proinsulin, and elevated levels of gastric inhibitory peptide and glycated hemoglobin (HbA1c) can be observed in normoglycemic individuals with TCF7L2 polymorphisms before the onset of type 2 diabetes. [21, 22]

Thus, while the specific mechanism driving the development of type 2 diabetes remains unclear, there is sufficient evidence to demonstrate that TCF7L2 variants strongly predict the development of type 2 diabetes and/or the progression to diabetes from impaired glucose tolerance. [20, 23]


Clinical Implications

Although genetic tests for TCF7L2 could help predict the incidence and the rate of onset of type 2 diabetes, [24] the strongest predictors continue to be positive family history, increased body mass index, increased blood pressure, and increased serum levels of triglycerides, apolipoprotein A-1, and liver enzymes, all of which precede inception of metabolic syndrome. [25] In fact, the predictive power of TCF7L2 variants disappears with lifestyle modifications or metformin treatment, while the improved insulin sensitivity resulting from these changes directly oppose the pathologic influence of TCF7L2 variants. [26] These data suggest that genetic susceptibility to type 2 diabetes as determined by TCF7L2 variants might prove an actionable indicator for early intervention and disease prevention. [23]

Researchers are also exploring whether TCF7L2 variants might serve as markers for tailoring customized therapeutic regimens. For example, DPP4 is a peptidase that degrades incretins such as GLP-1. [27] DPP4 inhibitors enhance incretin-stimulated insulin secretion and inhibit glucagon release, thereby helping to normalize blood glucose levels. If a negative influence on incretin secretion is confirmed as a major pathologic axis in TCF7L2 -driven type 2 diabetes, DPP4 inhibitors could potentially serve as a counterbalance and reverse the effects of TCF7L2 variants on incretin levels. [27] TCF7L2 polymorphisms have been associated with variation in the response to sulfonylurea treatment, but these effects are likely too modest to guide care. [28, 29]

Obviously, the clinical utility of TCF7L2 variants is associated with some caveats. First, the specific type 2 diabetes risk variants of TCF7L2 vary from population to population. [30] Similar effect sizes have been observed in a number of ethnic groups for the most commonly studied TCF7L2 variants, but the research must be expanded further beyond nonwhite populations. Second, although the effect sizes of TCF7L2 variants are relatively large, a much more accurate picture of risk stratification and therapeutic personalization would be informed by a larger collection of predisposition genes rather than TCF7L2 alone. 

Ultimately, TCF7L2 could prove a promising biomarker for disease prevention for those with an elevated genetic predisposition to type 2 diabetes. In the meantime, however, there is no clinical role for routine screening for TCF7L2, and the presence of TCF7L2 variants that are associated with increased risk of type 2 diabetes should be considered in combination with other known predictors when assessing a patient's individual risk for type 2 diabetes.