(PTFS10-02-25) Epigenetic Mediators of Diet and Insulin Resistance

Objectives: This study explores the connections between dietary factors and insulin resistance (HOMA-IR) through epigenetic mechanisms, focusing on DNA methylation signatures.

Methods: An epigenome-wide association study (EWAS) was conducted on 1,684 non-diabetic adults aged 57-75 from the Framingham Offspring Study. Associations between dietary factors (assessed via food frequency questionnaire) and DNA methylation sites (MS) were analyzed, with adjustments for confounders (age, sex, lifestyle) and multiple testing. Significant epigenetic mediators were evaluated using causal mediation models.

Results: The EWAS identified 35 MS linked to HOMA-IR, with 13 MS showing significant associations with dietary factors. Key mediators included cg17901584 (DHCR24), influenced by brown rice consumption, and cg22761431 (EFNB3), associated with wheat germ intake, both reducing HOMA-IR. Conversely, cg06690548 (SLC7A11) and cg06808571 (KCNH2) mediated increases in HOMA-IR linked to alcohol and low-calorie cola intake, respectively. Notably, the DHCR24 gene, crucial for cholesterol biosynthesis, was highlighted as a potential dietary target for reducing metabolic risk.

Conclusions: This study highlights the novel role of epigenetic mediators in linking dietary factors to insulin resistance, offering insights into previously underexplored molecular pathways. 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. Such advancements could significantly enhance prevention strategies for metabolic diseases.

Funding Sources: This research was funded by the United States Department of Agriculture (USDA), Agriculture Research Service (ARS) under agreement no: 8050-51000-107-000D.