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

Abstract

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 <i>Gad1</i>, suppressed <i>Gad1</i> expression, and elevated somatostatin (SST) protein in the pancreas in mice. Pancreas-specific double knockout (DKO) of <i>Tet2/3</i> recapitulates the IHG effects, causing <i>Gad1</i> hypermethylation and expression down-regulation, alongside impaired insulin secretion and glucose tolerance. Metabolomic analysis revealed that IHG and <i>Tet2/3</i> DKO reduced pancreatic GABA content. Gestational dietary GABA supplementation improved metabolic defects in both IHG and <i>Tet2/3</i> DKO models. scRNA-seq analysis of pancreatic islets showed that IHG or <i>Tet2/3</i> DKO down-regulated the β cell signature, whereas up-regulating δ cell-related genes, particularly <i>Sst</i>, led to the emergence of an <i>Ins2/Sst</i> double-positive cell population. β cell-specific deletion of <i>Sst</i> 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.