Epigenetically regulated pancreatic GABA-somatostatin signaling underlies gestational diabetes-induced glucose intolerance in offspring - PubMed
4 hours ago
- #GABA signaling
- #epigenetics
- #gestational diabetes
- Gestational diabetes mellitus (GDM) increases diabetes risk in offspring, but mechanisms are unclear.
- Intrauterine hyperglycemia (IHG) down-regulates DNA demethylases TET2/3 in fetal pancreatic islets, increasing DNA methylation of GABA synthesis gene Gad1.
- Tet2/3 double knockout (DKO) in pancreas mimics IHG effects, impairing insulin secretion and glucose tolerance.
- IHG and Tet2/3 DKO reduce pancreatic GABA content, while gestational GABA supplementation improves metabolic defects.
- scRNA-seq shows IHG or Tet2/3 DKO down-regulates β cell signature and up-regulates δ cell genes, particularly Sst.
- β cell-specific deletion of Sst rescues IHG-induced metabolic defects.
- GDM in humans is linked to reduced GABA in umbilical arterial blood.
- Epigenetically controlled GABA-SST signaling pathway contributes to GDM-induced diabetes risk in offspring.
- Dietary GABA supplementation is a potential intervention strategy.