From Molecular Insights to Clinical Management of Gestational Diabetes Mellitus-A Narrative Review

Abstract

Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy, affecting up to 14% of pregnancies globally. GDM is characterized by glucose intolerance that arises or is first identified during pregnancy and is linked to significant short- and long-term adverse outcomes for both mothers and their offspring. The pathophysiology of GDM involves more than maternal insulin resistance and β-cell dysfunction. It is influenced by complex interactions among placental hormones, adipokines, inflammatory mediators, and oxidative stress pathways. Additionally, placental-derived exosomes and metabolomic signatures have emerged as promising biomarkers for early prediction and monitoring of the disease. Despite advancements in clinical diagnosis and management, including lifestyle interventions and pharmacological treatments, current strategies are still inadequate to prevent complications for both mothers and newborns entirely. Recent molecular insights into GDM development have been explored, along with emerging biomarkers and potential therapies. This synthesis also considers prospects for precision medicine strategies that could significantly improve GDM management. The urgent need for improved prevention and treatment of GDM is evident. A deeper understanding of the molecular foundations of GDM is essential and urgent, as it may enhance clinical outcomes and provide opportunities for early prevention of intergenerational metabolic disease risk.

Keywords: adipokines; epigenetics; gestational diabetes mellitus; insulin resistance; placental biomarkers.

Figure 1

Molecular Mechanisms in GDM. (Figure created in BioRender. Assani, M. (2025) https://BioRender.com/0xnbu0m). Pregnancy-induced insulin resistance is driven by placental hormones (human placental lactogen (hPL), placental growth hormone, estrogen, progesterone, cortisol) and inflammatory cytokines (tumor necrosis factor α (TNF α), interleukin 6 (IL-6), interleukin 1β (IL-1β)) [10,20]. Inadequate β-cell adaptation due to mitochondrial dysfunction, and impaired incretin signaling leads to hyperglycemia. Dysregulated adipokines (↓ adiponectin, ↑ leptin, resistin, visfatin), oxidative stress, and epigenetic modifications (deoxyribonucleic acid (DNA) methylation, non-coding ribonucleic acids (RNAs)) further exacerbate disease and contribute to adverse maternal and fetal outcomes [10,21].

Figure 2

Clinical consequences and long-term outcomes of gestational diabetes mellitus (GDM). (Figure created in Canva, https://www.canva.com). The figure outlines GDM complications. During a pregnancy with GDM, complications such as preeclampsia, cesarean delivery, and neonatal issues (e.g., hypoglycemia) may occur. Long-term, women are more prone to type 2 diabetes, while offspring face obesity and diabetes. Future approaches focus on using precision medicine, omics, and digital health for early detection, risk assessment, and prevention.

Figure 3

Mind map of GDM. (Figure created in Canva, https://www.canva.com). The mind map provides a holistic overview of GDM, centered on five major domains: Clinical Management, Biomarkers, Pathophysiology, Outcomes, and Future Perspectives. Clinical Management covers diagnosis, lifestyle interventions, pharmacotherapy, and emerging therapies. Biomarkers include metabolomics, exosomes, microRNAs, classical markers, and immune biomarkers. Pathophysiology explores the mechanisms behind GDM, such as epigenetics, oxidative stress, adipokines, inflammation, beta-cell dysfunction, and insulin resistance. Outcomes highlight maternal short- and long-term risks, neonatal complications, and offspring’s long-term health impacts. Finally, Future Perspectives point toward omics, precision medicine, novel therapies, and digital health innovations. This overview demonstrates the complexity of GDM by combining clinical practice, biological mechanisms, patient outcomes, and future research directions into a unified, comprehensive model.