Transcription factor-7–like 2 (TCF7L2) is the most important type 2 diabetes susceptibility gene identified to date, with common intronic variants strongly associated with diabetes in all major racial groups
The polymorphism rs7903146 in the TCF7L2 gene confers the highest risk for type 2 diabetes. The T-risk allele is found in about 20% of the general population, nearly 30% in European and African, but only 2% in the Asian population . The risk, compared to the non-carrier alleles, CC profile, is 1.5 times higher in heterozygotes, CT profile and 2.4 times higher in homozygotes, TT profile( Figure 1)
Figure 1- Diagram of proposed pathophysiological pathway explaining how TCF7L2 risk genotypes predispose to type 2 diabetes. The risk genotype results in overexpression of TCF7L2 in pancreatic β cells, which in turn results in reduced insulin secretion. Reduced insulin secretion results in a predisposition to type 2 diabetes directly and also indirectly by increasing hepatic glucose output. Dotted arrows represent previous genetic associations. Solid arrows show observations reported by Lyssenko and colleagues
TCF7L2 polymorphisms are clearly guilty of predisposing to type 2 diabetes on the basis of strong, reproducible association in multiple populations and would appear to be the leader among a gang of susceptibility genes.
This gene creates a protein called transcription factor 7-like 2, which in turn binds to other genes to alter their expression. It has been shown through research to have an impact on how well you tolerate carbohydrates.
T allele affects insulin secretion which, over time, leads to higher levels of sugar in the blood – a distinctive sign of prediabetes and diabetes, but the specific pathogenic mechanism in this polymorphism is not yet fully clarified. It could be beta-cell dysfunction (specialized cells of the pancreas that produce and secretes insulin) or reducing the beta cell mass.
it has been shown that T-variant carriers of the TCF7L2 gene have a defect in the body’s response to food in the gut, which normally leads to insulin secretion by producing two hormons, GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitors peptide) also called incretins. The most important action of incretins is the stimulation of insulin secretion as well as the maintenance of glucose homeostasis. GLP-1 and GIP stimulate insulin-dependent glucose release from pancreatic B cells, with increased peripheral tissue glucose uptake and suppressed liver glucose production. The T-risk alleles in TCF7L2 are associated with impaired insulin secretion rather than insulin resistance.
Many studies have reported this association, including one( Cornelis MC et al., 2009)
In this study, the researchers recruited just over 3,000 nurses from a much larger longitudinal study taking place in the USA, called the Nurses Health Study (NHS). Of these 3000 subjects, 1140 had developed type-II diabetes, and the rest had not. As part of the NHS, which started in 1976 and recruited 121,700 female nurses, everyone involved was sent questionnaires every two years. These questionnaires often asked questions about food intake, and what the typical dietary habits of the nurses was like. From this, it was possible to find out not only how much fat, carbohydrate, and protein was typically consumed by these nurses, but also the type of each; of special interest to us in this case in the type of carbohydrate consumed – low Glycaemic Index (GI) or high GI. This allowed the researchers to see if there was an association with type of carbohydrates and the development of type-II diabetes, but also to see if this associated was enhanced or reduced by differences in the TCF7L2 gene.
What did they find? Firstly, a high-GI diet was found to be slightly more likely to cause the development of type-II diabetes than a low carbohydrate diet, which goes along with what we already know. However, when looking at TF7L2 genotype, this effect was much larger. Those nurses with two copies of the risk allele and following a diet with a high glycemic index were 2.7 times more likely to develop type-II diabetes than those with no risk alleles. With a low-GI diet, this risk was significantly reduced. It makes sense, therefore, that those carrying a risk allele of TCF7L2 should consume a diet with an overall low GI, prioritising carbohydrates from fibrous vegetables over simple sugars and refined gcarbohydrates.
TCF7L2 gene variation reflects adaptive dietary transition from hunter-gatherer to agricultural societies
Phylogenetic analysis showed that the type 2 diabetes-associated T allele of TCF7L2 at rs7903146 is the ancestral allele, whereas the protective C allele evolved more recently. The emergence of the C allele coincided with the onset of agriculture, indicating genetic adaptation to a carbohydrate-rich food environment. Before the transition to agriculture, our ancestors’ diets were mainly based on meat with some intake of carbohydrates from roots, tubers, fruits, nuts and seeds. With the development of agriculture, higher-starch foods, such as grains and cereals, became an important source of energy and meat and protein intake substantially decreased. Research has shown that C allele carriers gain more weight when their protein intake is less than 17% of total calories. This may stem from what was originally a selective advantage that helped provide weight stability and even promoted weight gain in C carriers when protein intake was limited. The ability to maintain weight during poorer nutritional conditions could have led to higher fitness and fertility, which in turn led to the positive selection that has been postulated for the C allele (Helgason et al., 2007).
The effects of TCF7L2 can be summarised as so:
CC genotype= No increased sensitivity to refined carbohydrates or saturated fat
CT genotype= Moderately increased sensitivity to both refined carbohydrates and saturated fats
TTgenotype= Associated with a significantly increased sensitivity to refined carbohydrates and saturated fat
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- Lyssenko, V., et al. 2007. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J. Clin. Invest. 117:2155–2163. doi:10.1172/JCI30706.
- . Helgason, A., et al. 2007. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat. Genet. 39:218–225.
- Cornelis MC1, Qi L, Kraft P, Hu FB. TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women. Am J Clin Nutr. 2009 Apr;89(4):1256-62.