The Double-Edged Sword of Gestational Insulin Resistance: Navigating Maternal Adaptation and Its Risks for Pregnancy...

Although much research focuses on the effects of hyperglycemia during pregnancy on maternal and offspring health, this narrative review specifically centers on the role of insulin resistance (IR) in pregnancy complications and offspring long-term health. Although hyperglycemia and IR are closely intertwined, this review deliberately prioritizes IR as a distinct yet interconnected factor driving metabolic dysfunction. During pregnancy, IR naturally increases to support fetal development. However, when IR becomes excessive, it can lead to metabolic disturbances and placental dysfunction. These conditions elevate the risk of pregnancy complications, impair fetal development, and adversely affect the long-term metabolic and cognitive health of the offspring. This review explores key factors influencing pregnancy-related IR, including genetic predisposition, lifestyle, physiological adaptations, hormonal fluctuations, and gut microbiota dysbiosis. It further examines how these factors worsen maternal metabolic imbalances and contribute to adverse pregnancy outcomes, including gestational hyperglycemia and hypertensive disorders, as well as their effects on neonatal complications and the long-term health of the offspring. Notably, this review is one of the first to address the transgenerational inheritance of IR, highlighting potential mechanisms such as epigenetic modifications, mitochondrial dysfunction, and the vertical transmission of altered maternal microbiota. In addition, we outline various preventive and therapeutic strategies aimed at mitigating these issues. These strategies include lifestyle changes, pharmacological treatments, nutritional supplementation, and emerging therapies such as mitochondrial-derived peptides and adipokine inhibitors. This narrative review provides a focused perspective on how pregnancy-related IR influences maternal and offspring health, offering insights for future clinical management and research.