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The journal Genes (Basel) has published a review of gene-diet interactions in type 2 diabetes mellitus (T2D), describing both the current understanding of genetic risk as well as potential approaches to target genetic risk with nutritional interventions. There is a clear role for hereditary risk in T2D, with first-degree relatives of people with T2D at 3-fold greater risk for developing it themselves. Yet, for most people with T2D, it is the accumulation of many genetic variants that appears to drive risk rather than a single mutation, as demonstrated in a number of genome-wide association studies (GWAS). As discussed in this review, this genetic risk can sometimes be modulated by dietary factors.
A number of key genes involved in T2D pathology have been identified, such as TCF7L2, GLIS3, PPARγ, etc. (reviewed here), many of which have roles in insulin signaling or regulation. For example, a single-nucleotide polymorphism (SNP) in the TCF7L2 gene (rs7903146) has been estimated to be the most impactful single variant on T2D risk, and its gene product is a transcription factor that influences pancreatic beta cell function and insulin secretion (via the WNT signaling pathway). The T allele of this SNP is recognized to be the higher risk variant for T2D; perhaps paradoxically, it is associated with a lower BMI among diabetics. In the PREDIMED study it was linked with a nearly 2-fold increase in risk for diabetes, but only among people without obesity. In other words, this allele is linked to an increase in the risk for diabetes (especially those without obesity), but a lower BMI (and heart disease risk) among diabetics.
The PREDIMED study, which was a randomized trial with over 7,000 participants, found a significant interaction between this SNP and the Mediterranean diet. People with two T alleles had higher fasting glucose levels than people with the CT or CC genotypes, but only when adherence to the Mediterranean diet was low, with similar findings for LDL cholesterol and triglycerides. Perhaps most importantly, the risk of stroke was nearly 3-fold higher among people with the TT genotype (compared to CC), but this risk was almost fully eliminated with a Mediterranean diet. A more recent smaller study may have elucidated one of the mechanisms for this risk negation; using a randomized cross-over design, it was found that in response to a low-fat diet, TT carriers had elevations in VLDL cholesterol compared to CC, but not while following a Mediterranean diet, and the latter more effectively reduced triglyceride-rich lipoprotein concentrations.
A study published in Scientific Reports also suggests a benefit of dietary recommendations tailored to DNA. Compared to a control group which received standard care, people receiving “DNA-personalized dietary advice” had a lower fasting plasma glucose and HbA1c by 6 months (though no difference was observed at 6 weeks). Similarly, an analysis of over 33,000 participants found a variant more common among people with African ancestry to modulate the relationship between carbohydrate intake and HbA1c levels. For those with the common variant, a lower HbA1c level was associated with a higher carbohydrate (vs. fat) intake.
This recent review also cites a 2022 paper that analyzed data from the Nurses' Health Studies and the Health Professionals Follow-up Study. A higher polygenic risk score was associated with a higher risk for diabetes in this study (29% higher per standard deviation), and a healthier diet (assessed by the Alternate Healthy Eating Index) was associated with a lower risk (13% per 10 point drop), but there was no interaction between the two. In other words, a less healthy diet increased the risk for diabetes among everyone, regardless of genetic risk. However, the study was observational with self-reported dietary intakes, which have important limitations.
Not discussed in this recent review is the role that gene-toxin interactions may have in influencing diabetes risk. For example, we know that both exposure to low levels of arsenic and the metabolism of arsenic influence risk. JAMA reported in 2008 a nearly 4-fold increase in risk for T2D with higher total urinary arsenic levels (80th vs. 20th percentile) after adjustment for seafood intake. Arsenic exposure has been found to have a synergistic interaction with genetically predicted risk, leading to a dysregulation and deterioration of glucose-insulin homeostasis. SNPs in the AS3MT and N6AMT1 genes appear to modify the methylation of arsenic, which in turn modifies risk. A variant in N6AMT1, for example, influences the efficiency of arsenic detoxification, and was shown to interact with arsenic exposure to modify the risk for gestational diabetes in a population of over 1,600 pregnant women. The gene product of N6AMT1 is a methyltransferase, recently determined to be involved in mitochondrial biogenesis.
Additionally, variants in the gene mentioned previously (TCF7L2) have been shown to interact with tobacco smoking to influence diabetes risk, at least among people of European ancestry. Data from over 61,000 participants in 19 cohort studies found that smoking interacted with at-risk alleles in this gene, with a synergistic effect on diabetes risk. Hopefully, as the predictive value and understanding of gene function continue to increase, more targeted nutritional and environmental interventions can help to reduce the risk of developing T2D as well as its morbidity.
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