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

Abstract

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.

Keywords: Hepatokines; Liver; Metabolic sensor; Fetal metabolic imprinting; Epigenetic reprogramming; Intrauterine exposure; Insulin resistance in pregnancy

Core Tip: Gestational diabetes mellitus does not only affect maternal glucose metabolism, but it can also program lifelong metabolic vulnerabilities in the offspring. This article emphasizes the underappreciated role of the maternal liver as a metabolic sensor that detects pregnancy-related physiological stress and modulates systemic signals accordingly. When impaired by gestational diabetes mellitus, the maternal liver becomes a source of maladaptive endocrine, inflammatory, and metabolic cues that are transmitted to the fetus. These signals can reprogram fetal liver development and increase the risk of non-alcoholic fatty liver disease and type 2 diabetes mellitus in later life. Recognizing the liver’s central role in this process opens new avenues for preventive and therapeutic strategies targeting both maternal and offspring health.