A recent longitudinal study has found that puberty can alter the epigenetic profiles of children in ways that are linked to either worsening or improving insulin resistance (IR). The research, published in Cardiovascular Diabetology, investigated how changes in DNA methylation during puberty might signal future risk for cardiometabolic diseases.
Insulin resistance occurs when tissues do not respond effectively to insulin, leading to problems with glucose metabolism. This condition is often associated with obesity and increases the risk of developing type 2 diabetes and cardiovascular disease. Previous studies have indicated that persistent IR during puberty is strongly connected to early onset type 2 diabetes among youth. While certain genetic variants are known to influence this risk, they explain only a small portion of it; epigenetic factors such as DNA methylation play a significant role by mediating environmental influences on gene expression.
The current study was part of the PUBMEP project and included Spanish children who were followed from pre-puberty through puberty. Researchers used established tools—HOMA-IR and QUICKI—to assess IR status, applying sex- and stage-specific cut-offs for classification. The analysis compared these clinical measures with genotype and DNA methylation data using linear models.
Participants were divided into five groups based on their IR trajectories related to obesity. These groups were combined with additional cross-sectional samples for broader analysis. The study identified 120 CpG sites where changes in DNA methylation correlated with IR at puberty. Notably, children whose IR worsened at puberty showed increased methylation (hypermethylation), while those whose IR improved exhibited decreased methylation (hypomethylation).
Groups experiencing new-onset or persistent IR at puberty had higher levels of HOMA-IR, fasting insulin, fat mass index, leptin, and inflammatory markers compared to those without pubertal IR. Blood pressure differences were also most pronounced between these groups.
Researchers found that 14 CpG sites linked to pubertal IR were also associated with other metabolic traits such as adiposity, high blood sugar, or elevated blood pressure—suggesting shared underlying epigenetic mechanisms across multiple cardiometabolic conditions.
Some newly identified methylation sites were located within genes including PEPD, TSC2, EGLN3, EHD2, SLC2A9, and VASN. These genes are involved in pathways related to vascular signaling and nutrient sensing but had not previously been connected to pediatric insulin resistance.
While some DNA methylation changes appeared influenced by nearby genetic variants according to mQTL analysis, most seemed independent of genetics—implying a stronger role for environmental or metabolic factors during puberty.
The researchers noted several limitations: the relatively small sample size; use of whole blood rather than tissue-specific samples; absence of external validation cohorts; and potential confounding factors such as pollution exposure or maternal body mass index that could affect epigenetic variation.
"Despite the lack of causal inferences, these observations suggest the presence of modifiable epigenetic markers in obesity-related IR," according to the authors. "These trajectory-linked methylation patterns were consistent with pubertal cross-sectional differences between IR and non-IR adolescents."
They concluded: "This longitudinal study shows that in children, distinct DNA methylation profiles mirror the presence of IR and its trajectory during the pubertal transition." The findings point toward possible future strategies targeting both metabolic parameters and epigenetic modifications as preventive measures against cardiometabolic disease.
