Liver as a metabolic sensor in gestational diabetes: Implications for offspring's liver and diabetes risk

Gestational diabetes mellitus (GDM) is increasingly recognized not only for its immediate obstetric complications but also for its long-term metabolic consequences in both mothers and their offspring. Traditionally, research has emphasized the roles of pancreatic β-cell dysfunction and placental dysregulation in GDM. However, emerging evidence highlights the maternal liver as a central metabolic hub during pregnancy coordinating glucose, lipid, and hormonal adaptations essential for fetal development. This review synthesizes current findings on how GDM disrupts the maternal liver's adaptive roles, transforming it from a metabolic coordinator into a source of maladaptive endocrine, inflammatory, and nutrient signals. It outlines key mechanistic pathways through which maternal hepatic dysfunction may increase offspring susceptibility to non-alcoholic fatty liver disease and type 2 diabetes mellitus. These include hepatokine dysregulation, altered lipid metabolism, impaired insulin signaling, inflammatory and oxidative stress pathways, and epigenetic and transcriptomic reprogramming. In addition, it explores novel axes such as the gut-liver-placenta interplay, bile acid signaling disruptions, endoplasmic reticulum stress responses, and extracellular vesicle-mediated communication. By reframing the maternal liver's role in GDM pathophysiology, this review identifies critical windows for early clinical intervention and highlights the potential for liver-focused strategies to prevent the intergenerational transmission of metabolic disease.