The Link Between Diabetes and High-Carb Foods (TCF7L2)

The TCF7L2 (transcription factor 7 like 2) gene, previously known as TCF4, codes for a vital transcription factor. It controls the expression of other genes in digestive organs such as the gut and pancreas, with a particular role in glucose metabolism and insulin secretion [R, R].

This gene has the strongest association with type 2 diabetes observed so far. Specific variants in this gene, such as rs7903146, correlate with increased diabetes rates among all major populations [R, R, R].

As you are about to learn in this post, the impact of this gene on diabetes can be reduced—or worsened—by the type of food we eat.

How Does TCF7L2 Affect Blood Sugar?

From what we currently know, TCF7L2 variants can impair insulin secretion but not insulin sensitivity. This gene controls the activity of GLP-1, an intestinal peptide that stimulates insulin secretion in response to food [R, R, R].

During and after each meal, the body signals an enhanced secretion of insulin to balance blood sugar levels. GLP-1 is one of the crucial mediators of this response, known as incretins [R].

TCF7L2 variants—such as the “T” allele at rs7903146—likely prevent GLP-1 from stimulating the pancreas, raising insulin levels, and reducing blood sugar after meals [R, R].

Foods high in sugar and quickly digestible carbs have a high glycemic index (GI) and glycemic load (GL). They drastically increase blood glucose and insulin demand, thus magnifying the impact of TCF7L2 [R].

_{Source: https://www.glycemicindex.com}

Specific TCF7L2 variants hinder GLP-stimulated insulin secretion in response to food. This effect comes to light after meals high in sugar and quickly digestible carbs.

Evolutive Perspective

The diabetes-associated “T” allele at rs7903146 is ancestral, while the other (C) evolved more recently. As we were transitioning from hunter-gatherers to agriculture-based societies, TCF7L2 adapted to carbohydrate-rich diets [R].

People with the variant allele metabolized high-starch foods such as grains more efficiently, which brought them an evolutionary advantage. The ancestral “T” allele is now much less common as it doesn’t “handle” modern diets well.

In two studies of 4,000 participants, tailored nutritional and lifestyle interventions were able to lower or even remove the negative impact of TCF7L2 variants (rs12255372 and rs7903146) on diabetes risk. Patients were educated and motivated to reduce weight, exercise more, and improve their diets [R, R].

Dietary advice was general: it included a reduction in calories and saturated fat while increasing the consumption of vegetables and other fiber-rich foods. Given the study designs, it’s hard to estimate the impact of specific dietary changes on TCF7L2-associated diabetes risk.

Glycemic Index and Glycemic Load

A clinical trial of over 3,000 women took this further and examined the effect of food glycemic index (GI) and glycemic load (GL) on TCF7L2 variants:

Women with the “TT” genotype at rs12255372 who consumed foods with the highest GI and GL had 2.7 higher diabetes rates, compared with the “GG” carriers. On the other hand, those with the lowest GI and GL had only 1.66 and 1.82 higher incidence, respectively [R].

The authors concluded that carbohydrate quality and quantity might modify the association between TCF7L2 variants and diabetes in women. The same likely goes for men, but studies are yet to confirm that [R].

People with the “T” alleles at rs12255372 and rs7903146 have increased diabetes rates. The consumption of foods with high GI and GL may worsen the effects of TCF7L2 variations.

Whole Grains and Dietary Fiber

Increased consumption of whole grains and dietary fiber generally reduces the risk of diabetes, but the same may not hold for people with TCF7L2 risk alleles [R, R].

Namely, in a study of over 3,000 people, the intake of whole grains was inversely associated with diabetes rates only among the “CC” carriers at rs7903146. The authors concluded that “the “T” allele negated the protective effect of whole-grain intake” [R].

A large Sweedish study followed 24,800 participants for 12 years and examined the impact of dietary fiber intake on the TCF7L2-diabetes link.

People with the “T” allele at rs7903146 who ate less fiber had 24% higher diabetes rates, compared with the “CC” genotype. High fiber intake more than doubled their diabetes rates (from 24 to 56%) while having a protective effect among the “CC” carriers [R].

According to the authors, the “T” allele may prevent dietary fiber from increasing GLP-1 and stimulating insulin secretion.

Increased intake of whole grains and dietary fiber reduces the risk of diabetes in general, but it may have the opposite effect among the “T” allele carriers at rs7903146.

SNP Summary and Table

Primary SNP:

TCF7L2 rs7903146

• ‘C’ = no association with diabetes; good response to whole grains and fiber
• ‘T’ = associated with diabetes; poor response to whole grains and fiber

Other Important SNP:

TCF7L2 rs12255372

• ‘G’ = no association with diabetes; typical response to moderate- and high-GI foods
• ‘T’ = associated with diabetes; poor response to moderate- and high-GI foods

Population Frequency

These two variants are almost always inherited together, which means they act as a single genetic factor.

About 40% of European descendants carry one copy of the problematic “T” allele while 10-12% carry both copies. In East-Asian populations, this allele is much less common (2-4%).