Gestational diabetes mellitus alters DNA methylation profiles in pancreas of the offspring mice

Gestational diabetes mellitus (GDM), which has an increasing global prevalence, contributes to the susceptibility to metabolic dysregulation and obesity in the offspring via epigenetic modifications. However, the underlying mechanism remains largely obscure. The current study established a GDM mice model to investigate the alternations in the metabolic phenotypes and genomic DNA methylation in the pancreas of the offspring. We found that in the GDM offspring, intrauterine hyperglycemia induced dyslipidemia, insulin resistance, and glucose intolerance. Meanwhile, altered DNA methylation patterns were exhibited in the pancreas and many differentially methylated regions (DMRs)-related genes were involved in glycolipids metabolism and related signaling pathways, including Agap2, Plcbr, Hnf1b, Gnas, Fbp2, Cdh13, Wnt2, Kcnq1, Lhcgr, Irx3, etc. Additionally, the overall hypermethylation of Agap2, verified by bisulfite sequencing PCR (BSP), was negatively correlated with its mRNA expression level. In conclusion, these findings suggest that the DNA methylation changes in the pancreatic genome of the GDM offspring may be associated with the glycolipid metabolism abnormalities, T2DM susceptibility, and obesity in the adult GDM offspring.