# Epigenetic mediators of diet and lifestyle and insulin resistance

## TL;DR

This study finds that specific DNA methylation sites mediate the effects of diet and lifestyle on insulin resistance, suggesting potential for personalized dietary interventions.

## Contribution

The study identifies novel DNA methylation sites that mediate the relationship between diet/lifestyle and insulin resistance.

## Key findings

- 35 DNA methylation sites were linked to insulin resistance, with 13 specifically associated with dietary factors.
- Brown rice, wheat germ, and lactose were linked to decreased insulin resistance via specific DNA methylation sites.
- Alcohol and low-calorie cola were associated with increased insulin resistance through epigenetic mediation.

## Abstract

Implementing personalized dietary interventions has become important as emerging evidence indicates that dietary and lifestyle-dependent epigenetic modifications affect insulin resistance.

An epigenome-wide association study (EWAS) was conducted on 1,684 non-diabetic adults aged 57–75 from the Framingham Offspring Study (FOS). Associations between dietary and lifestyle factors (assessed via food frequency questionnaire) and DNA methylation sites (DNA-MS) were analyzed, with adjustments for confounders (age, sex, lifestyle) and multiple testing. Significant epigenetic mediators were evaluated using causal mediation models. Validation was executed using the Genetics of Lipid-Lowering Drugs and Diet Network Study (n = 945).

The EWAS identified 35 DNA-MS linked to HOMA-IR, with 13 DNA-MS showing significant associations with dietary factors in the FOS. Key DNA-MS including cg17901584 (DHCR24), influenced by brown rice (natural indirect effect: β ± SE, -0.02 ± 0.01, p = 0.0003), cg22761431 (EFNB3) by wheat germ (-0.01 ± 0.003, p = 0.001), and cg00574958 (CPT1A) associated with lactose (-0.001 ± 0.0003, p = 0.0001) intakes, all correlated with decreased HOMA-IR. Other DNA-MS, cg06808571 (KCNH2), cg06690548 (SLC7A11), and intergenic cg07504977, mediated increases in HOMA-IR linked to intakes of low-calorie cola (0.003 ± 0.001, p = 0.001), alcohol (0.01 ± 0.001, p = 9.0E-11), and palmitoleic acid (0.03 ± 0.01, p = 9.0E-05), respectively. In the GOLDN study, alcohol intake mediated by cg06690548 methylation in SLC7A11 was positively associated with HOMA-IR. Notably, the DHCR24 gene, crucial for cholesterol biosynthesis, was highlighted as a potential dietary target for reducing metabolic risk.

The identification of specific DNA methylation sites, such as those in DHCR24 and EFNB3, provides supportive evidence for the mechanistic basis of known dietary effects on metabolic health. These findings not only reinforce the importance of diet in managing insulin resistance but also open avenues for personalized dietary interventions tailored to an individual’s epigenetic profile.

The online version contains supplementary material available at 10.1186/s12263-025-00792-7.