Maternal type 1 diabetes may protect children from developing the disease

By Dr. Liji Thomas, MDReviewed by Lauren HardakerNov 10 2025

Scientists uncover how exposure to a mother’s type 1 diabetes during pregnancy may epigenetically “reprogram” her child’s immune system, offering new clues to lifelong protection against the disease.

Study: Blood methylome signatures in children exposed to maternal type 1 diabetes are linked to protection against islet autoimmunity. Image credit: Natalia Deriabina/Shutterstock.com

Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by dysregulation of blood glucose due to the deficiency of insulin. A recent study published in the journal Nature Metabolism examined nearly 2,000 mother-offspring dyads, comparing the offspring of one maternal cohort having T1D with those of the non-T1D maternal cohort. The results of the analysis revealed epigenetic changes that could help protect children born to mothers with T1D against the condition, compared to the other cohort.

How early environments shape health

Environmental factors can interfere with early development and have lasting effects on health. These outcomes are often driven by epigenetic mechanisms, such as DNA methylation, which alter gene expression without altering the genetic code itself. Such modifications may explain how a mother’s lifestyle and medical conditions, like smoking, obesity, or higher stress during pregnancy, can influence her child’s biology and long-term well-being.

T1D is a very common chronic illness that often presents in childhood and adolescence. It is the result of autoimmune antibodies, usually produced during the first year of life, that destroy the beta cells of the pancreatic islets of Langerhans. Since these cells produce insulin, the hormone that regulates blood glucose levels, islet destruction leads to T1D.

Genetic and environmental factors work together to trigger this autoimmune response. T1D is 8 to 15-fold more common in people whose first-degree relatives have the condition, but it is differentially expressed depending on whether the affected member is a parent or sibling.

However, children of mothers with T1D are less likely to develop islet autoimmunity before the age of two years. The current study sought to explore the epigenetic changes associated with this phenomenon.

Mother-child analysis

The study compared 790 dyads composed of mothers with T1D and their offspring with 962 dyads of non-T1D mothers and their children. All the children in the study were at a higher risk of T1D, either because they had a first-degree relative with the condition or due to a higher genetic risk score.

The median age of the children in the study was 2.1 years in the BABYDIAB/BABYDIET cohort and 1.5 years in the POInT cohort, respectively.

Key DNA methylation discoveries

The methylation samples showed an age of 0.5 years below the chronological age in both studies, irrespective of the maternal T1D status. However, different levels of DNA methylation were demonstrated at multiple genetic loci and regions in children born to mothers with T1D vs the other mothers.

For instance, the Homeobox A gene cluster was differentially methylated in children of mothers with T1D. These proteins form part of a large group of transcription factors active in early development, including fetal and infant growth. Some are associated with inflammation and the accumulation of fat.

Overall, 566 CpG sites were significantly differentially methylated between the groups, though 1,677 sites were associated with maternal T1D across analyses. Approximately 14 of these sites were known to be linked to and affected by maternal T1D. These modifications were not observed in much older children of mothers with T1D.

These epigenetic alterations occurred in regions involved in transcriptional regulation, primarily affecting immune-related genes, particularly those associated with the molecule MBD2, which binds to hypermethylated regions to influence transcription. They also affect the development of autoimmunity.

Similarly, epigenetic changes may be implicated in the regulation of 15 genes that increase susceptibility to T1D. Several of these were within the MHC region of chromosome 6, while others were HLA-related.

Some of the altered loci belonged to sites already known to be associated with T1D-related methylation, and others to protein biomarkers. This suggests that such epigenetic changes are important factors in the immune dysfunction underlying T1D.

As a result, methylation propensity scores (MPSs) for these loci were associated with a lower risk of developing islet autoimmunity in children of mothers without T1D.

Overall, the study demonstrates that maternal T1D is associated with significant epigenetic changes in the offspring's DNA, detectable at 18 months or more following exposure. This is not the case with children whose fathers or siblings have this condition. Moreover, the presence of maternal T1D is protective against islet autoimmunity in the offspring.

These methylation changes were associated with immune-related genes and those linked to T1D susceptibility. Thus, the risk of islet autoimmunity is influenced by environmental factors through the DNA methylation of susceptibility genes for T1D. The scientists created a methylation score for this purpose, which reflected the protective effect seen in children who were not exposed to maternal T1D but carried a higher genetic risk for the condition.

Most of the methylation differences represented hypermethylation and were found in transcriptionally relevant immune regions, consistent with an epigenetic mechanism of immune tolerance.

Next steps in epigenetic research

Together, these findings highlight pathways through which maternal T1D may confer protection against islet autoimmunity in offspring and suggest that environmental factors can influence T1D risk through epigenetic modifications of T1D susceptibility loci.

The study employed an associative approach and used whole-blood methylation data from predominantly European cohorts; therefore, further research is necessary to identify causal mechanisms and validate these findings in diverse populations.

Further studies are needed to investigate how epigenetic alterations in target genes influence the development of autoimmunity in at-risk children, potentially identifying a therapeutic target. Research is also necessary to understand whether other environmental factors that affect the risk of T1D are likewise influenced by epigenetic modification. Meanwhile, epigenetic scores like the MPS may be incorporated into polygenic risk scores to help predict the risk of T1D and islet autoimmunity.

Download your PDF copy now!