Epigenetically regulated pancreatic GABA-somatostatin signaling underlies gestational diabetes–induced glucose intolerance in offspring

Gestational diabetes mellitus (GDM) can increase the risk for diabetes in offspring, but the mechanisms underlying the effects of intrauterine hyperglycemia (IHG) on the fetus remain unknown. Here, we show that IHG down-regulated DNA demethylases TET2/3 in fetal pancreatic islets, increased DNA methylation of γ-aminobutyric acid (GABA) synthesis gene Gad1 , suppressed Gad1 expression, and elevated somatostatin (SST) protein in the pancreas in mice. Pancreas-specific double knockout (DKO) of Tet2/3 recapitulates the IHG effects, causing Gad1 hypermethylation and expression down-regulation, alongside impaired insulin secretion and glucose tolerance. Metabolomic analysis revealed that IHG and Tet2/3 DKO reduced pancreatic GABA content. Gestational dietary GABA supplementation improved metabolic defects in both IHG and Tet2/3 DKO models. scRNA-seq analysis of pancreatic islets showed that IHG or Tet2/3 DKO down-regulated the β cell signature, whereas up-regulating δ cell–related genes, particularly Sst , led to the emergence of an Ins2/Sst double-positive cell population. β cell–specific deletion of Sst rescued IHG-induced metabolic defects. In humans, GDM was associated with reduced GABA content in the umbilical arterial blood. These results uncover an epigenetically controlled pancreatic GABA-SST signaling pathway that may contribute to the GDM-induced increase in offspring diabetes risk and identify dietary GABA supplementation as a potential interventional strategy.