Gestational diabetes: from pathogenesis to therapeutic intervention

Gestational diabetes mellitus (GDM), affecting up to 15% of pregnancies worldwide, is a complex metabolic disorder arising from the interaction of pregnancy-induced insulin resistance and inadequate pancreatic β-cell compensation. This review synthesizes current advances in understanding the pathogenesis and therapeutic strategies of GDM. Mechanistically, GDM develops through a multifactorial network involving placental hormone–driven insulin resistance, impaired β-cell adaptive remodeling, genetic susceptibility, and epigenetic modifications that alter key metabolic regulators such as INSR and PDX1. Increasing evidence further implicates immunometabolic dysregulation—including neutrophil extracellular trap formation and placental inflammation—along with gut microbiota dysbiosis characterized by depletion of butyrate-producing bacteria and enrichment of lipopolysaccharide-producing taxa. Additional emerging contributors include circadian rhythm disruption and exposure to environmental endocrine-disrupting chemicals, both of which can interfere with glucose homeostasis and insulin signaling. These interacting mechanisms contribute not only to maternal hyperglycemia but also to adverse maternal and fetal outcomes, including macrosomia, preterm birth, and long-term cardiometabolic risk in both mothers and offspring. Current management strategies rely primarily on lifestyle interventions and pharmacotherapies such as insulin and metformin; however, novel therapeutic approaches—including GLP-1 receptor agonists, SGLT2 inhibitors, and microbiome-targeted interventions—are being explored, although their safety in pregnancy requires further validation. Looking forward, integrating multi-omics technologies, early biomarkers, and digital health monitoring may enable precision medicine approaches for earlier diagnosis, mechanistic subtyping, and individualized treatment of GDM, ultimately reducing its intergenerational metabolic burden.