The TCF7L2 Gene: Dietary Prevention of T2DM

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Type 2 diabetes (T2DM) is associated with increased morbidity and mortality, and its growing prevalence represents a major public health concern. T2D results from a combination of genetics and the exposure to external factors (i.e., diet, exercise, and stress). Multiple T2D-related genes have been i...

Type 2 diabetes (T2DM) is associated with increased morbidity and mortality, and its growing prevalence represents a major public health concern. T2D results from a combination of genetics and the exposure to external factors (i.e., diet, exercise, and stress). Multiple T2D-related genes have been identified, but they explain only ~10% of the estimated T2D heritability. Therefore, it has been proposed that interactions between genetic and environmental factors contribute to the missing heritability. The identification of these gene-environment interactions could provide a breakthrough in the prevention of T2D and its complications through the implementation of novel nutrigenomics approaches. The rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene is the most replicated T2D-associated SNP. However, the mechanism associating TCF7L2 with T2D remains unknown. Moreover, there is little knowledge of how diet modulates this association. A better understanding is crucial for improving existing, or designing new interventions for T2D prevention. The current knowledge supports the notion that subjects homozygous for the deleterious allele (TT) have a higher risk of T2D than subjects homozygous for the common allele (CC). Furthermore, there is a gene-diet interaction between this SNP and Mediterranean diet (MedDiet) on fasting glucose and lipids. Thus, a higher MedDiet adherence neutralizes the effects of the deleterious TT genotype. Moreover, after ~5 years, TT subjects consuming a low-fat diet have higher incidence of stroke than CC subjects, whereas this association is annulled in TT subjects consuming a MedDiet. the objective of this study is to validate these findings under practical conditions similar to those encountered in clinical practice and to identify biological mechanisms involved in such interactions. For this purpose, a four-week study will be conducted to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, and inflammation (CRP) in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene. The (2) one-week study diets, one Mediterranean diet (MedDiet) based and the other low-fat based will be separated by a (1) week return to a regular habitual diet. The specific aims include: To investigate whether the TCF7L2-by-diet interaction in relation to T2D and cardiovascular disease (CVD) risk factors can be validated in the context of a more realistic scenario of personalized dietary advice based on genetic information (nutrigenomics). To elucidate the molecular mechanisms responsible for these gene-by-diet interactions using deep phenotyping (i.e., metabolomics). The hypothesis is that genetics can offer precise information about which healthy diet (low-fat or Mediterranean) can deliver real benefits on an individual basis.

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