Dietary Macronutrient Intake May Influence the Effects of TCF7L2 rs7901695 Genetic Variants on Glucose Homeostasis and Obesity-Related Parameters: A Cross-Sectional Population-Based Study

Transcription factor-7-like 2 (TCF7L2) is one of the most important susceptibility genes for type 2 diabetes mellitus (T2DM). The aim of our cross-sectional population-based study was to analyze whether daily macronutrient intake may influence the effects of the TCF7L2 rs7901695 genotype on glucose homeostasis and obesity-related parameters. We recruited 810 participants (47.5% men and 52.5% women), 18-79 years old (mean age, 42.1 (±14.5) years), who were genotyped for the common TCF7L2 rs7901695 single-nucleotide polymorphism (SNP), and anthropometric measurements, body composition, body fat distribution (visceral (VAT) and subcutaneous adipose tissue (SAT) content), blood glucose and insulin concentrations after fasting and during OGTTs, and HbA1c were assessed. The VAT/SAT ratio, HOMA-IR (homeostatic model assessment of insulin resistance), HOMA-B (homeostatic model assessment of β-cell function), and CIR30 (corrected insulin response) were calculated. The daily macronutrient intake was evaluated based on 3-day food-intake diaries. Daily physical activity was evaluated based on a validated questionnaire. We performed ANOVA or Kruskal-Wallis tests, and multivariate linear regression models were created to evaluate the effects of dietary macronutrient intake on glucose homeostasis and obesity-related parameters in carriers of the investigated genotypes. This study was registered at ClinicalTrials.gov as NCT03792685. The TT-genotype carriers stratified to the upper protein intake quantiles presented higher HbA1c levels than the CT- and CC-genotype participants in the same quantiles (p = 0.038 and p = 0.022, respectively). Moreover, we observed higher HOMA-IR (p = 0.014), as well as significantly higher blood glucose and insulin concentrations, during the OGTTs for those in the upper quantiles, when compared to subjects from the lower quantiles of protein intake, while the CC-genotype carriers presented significantly lower HbA1c (p = 0.033) and significantly higher CIR30 (p = 0.03). The linear regression models revealed that an increase in energy derived from proteins in TT carriers was associated with higher HbA1c levels (β = 0.37 (95% CI: 0.01-0.74, p = 0.05)), although, in general, carrying the TT genotype, but without considering protein intake, showed an opposite tendency-to lower HbA1c levels (β = -0.22 (95% CI: 0.47 to -0.01, p = 0.05). Among the subjects stratified to the lower quantile of carbohydrate intake, the TT-genotype individuals presented higher HbA1c (p = 0.041), and the CC-genotype subjects presented higher VAT (p = 0.033), lower SAT (p = 0.033), and higher VAT/SAT ratios (p = 0.034). In both the CC- and TT-genotype carriers, we noted higher VAT (p = 0.012 and p = 0.0006, respectively), lower SAT (p = 0.012 and p = 0.0006, respectively) and higher VAT/SAT ratios (p = 0.016 and p = 0.00062, respectively) when dietary fat provided more than 30% of total daily energy intake, without any differences in total body fat content. Our findings suggest that associations of the common TCF7L2 SNP with glucose homeostasis and obesity-related parameters may be dependent on daily macronutrient intake, which warrants further investigations in a larger population, as well as interventional studies.