Unveiling Gestational Diabetes: An Overview of Pathophysiology and Management

Abstract

Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women.

Keywords: dietary intervention; gestational diabetes mellitus; glucose intolerance; hyperglycemia; insulin resistance; maternal health; neonatal outcomes; preeclampsia.

Figure 1

Outcomes of gestational diabetes mellitus (GDM) on mothers and offspring: This figure illustrates short-term and long-term outcomes of GDM for both mothers and their offspring. For mothers, short-term outcomes include increased risk of cesarean delivery and hypertensive disorders of pregnancy, while long-term outcomes encompass a heightened risk of developing type 1 diabetes (T1D) or type 2 diabetes (T2D). For offspring, short-term outcomes highlight the risks of macrosomia, neonatal hypoglycemia, and respiratory distress syndrome. Long-term outcomes for offspring demonstrate an increased risk of T1D or T2D and metabolic syndrome into adulthood. Created in BioRender. https://BioRender.com/n76l932 (accessed on 2 December 2024).

Figure 2

A schematic representation of insulin signaling: When insulin binds to its receptor (IR), it triggers activation of IRS-1. Adiponectin enhances activation of IRS-1 via the AMP-activated protein kinase (AMPK) pathway. Activated IRS-1 then stimulates phosphatidylinositol-3-kinase (PI3K), which converts phosphatidylinositol-4, 5-bisphosphate (PIP2) into phosphatidylinositol-3-, 4-, 5-phosphate (PIP3). PIP3 subsequently activates Akt2, leading to the translocation of GLUT4 transporters to the cell surface and facilitating glucose entry into the cell. On the other hand, pro-inflammatory cytokines activate protein kinase C (PKC) through the IκB kinase (IKK), which then inhibits IRS-1 leading to disruption in insulin signaling. Created in BioRender. https://BioRender.com/a92r994 (accessed on 2 December 2024).

Figure 3

A comparison of β-cell function and insulin sensitivity in normal and GDM pregnancies: During normal pregnancy, β-cells undergo expansion through hyperplasia and hypertrophy to accommodate the increased metabolic requirements. Concurrently, there is an increase in blood glucose levels due to reduced insulin sensitivity. After pregnancy, β-cells, blood glucose, and insulin sensitivity generally revert to their original state. However, in GDM, β-cells are unable to adequately adapt to the demands of pregnancy, causing an increase in blood glucose levels due to decreased insulin sensitivity. GDM resolves postpartum as the primary drivers of insulin resistance—placental hormones such as human placental lactogen (hPL) and progesterone—are no longer present. However, residual β-cell dysfunction, persistent low-grade inflammation, and metabolic abnormalities remain in many women, increasing their long-term risk for type 2 diabetes (T2D). Created in BioRender. https://BioRender.com/o66i148 (accessed on 2 December 2024).