Epigenetic mediators of diet and lifestyle and insulin resistance

Authors: Akinlawon, Oladimeji; Parnell, Laurence; LIU, FANG - Tufts University; ARNETT, DONNA - University Of South Carolina; ORDOVAS, JOSE - Tufts University; Lai, Chao Qiang

Submitted to: Genes and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/27/2025
Publication Date: 1/24/2026
Citation: Akinlawon, O.J., Parnell, L.D., Liu, F., Arnett, D.K., Ordovas, J.M., Lai, C. 2026. Epigenetic mediators of diet and lifestyle and insulin resistance. Genes and Nutrition. https://doi.org/10.1186/s12263-025-00792-7.
DOI: https://doi.org/10.1186/s12263-025-00792-7

Interpretive Summary: Can our diet influence how our genes affect blood sugar? Scientists studied over 1,600 older adults to understand how what we eat and drink might influence how our bodies handle blood sugar and insulin. They focused on DNA methylation—a natural way our bodies can switch genes on or off without changing the DNA itself. This process can be shaped by our diet and lifestyle. They found 35 sites in our DNA where these gene switches were linked to insulin resistance. Thirteen of these were also tied to specific foods or drinks. For example, eating brown rice, dairy (lactose), and wheat germ was linked with better insulin sensitivity. In contrast, alcohol, low-calorie sodas, and certain fats were linked to poorer insulin response. These findings suggest that our diet may influence blood sugar control by changing how our genes behave. This opens the door to developing more personalized nutrition strategies based on how individual genes respond to food.

Technical Abstract: Background: Implementing personalized dietary interventions has become important as emerging evidence indicates that dietary and lifestyle-dependent epigenetic modifications affect insulin resistance. Methods: 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). Results: 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: beta ± 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. Conclusion: 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.