Cellular and Molecular Pathophysiology of Gestational Diabetes

Abstract

Gestational diabetes (GD) is a metabolic disorder characterized by glucose intolerance during pregnancy, significantly impacting maternal and fetal health. Its global prevalence is approximately 14%, with risk factors including obesity, family history of diabetes, advanced maternal age, and ethnicity, which are linked to cellular and molecular disruptions in glucose regulation and insulin resistance. GD is associated with short- and long-term complications for both the mother and the newborn. For mothers, GD increases the risk of developing type 2 diabetes, cardiovascular diseases, and metabolic syndrome. In the offspring, exposure to GD in utero predisposes them to obesity, glucose intolerance, and metabolic disorders later in life. This review aims to elucidate the complex cellular and molecular mechanisms underlying GD to inform the development of effective therapeutic strategies. A systematic review was conducted using medical subject headings (MeSH) terms related to GD's cellular and molecular pathophysiology. Inclusion criteria encompassed original studies, systematic reviews, and meta-analyses focusing on GD's impact on maternal and fetal health, adhering to PRISMA guidelines. Data extraction captured study characteristics, maternal and fetal outcomes, key findings, and conclusions. GD disrupts insulin signaling pathways, leading to impaired glucose uptake and insulin resistance. Mitochondrial dysfunction reduces ATP production and increases reactive oxygen species, exacerbating oxidative stress. Hormonal influences, chronic inflammation, and dysregulation of the mammalian target of rapamycin (mTOR) pathway further impair insulin signaling. Gut microbiota alterations, gene expression, and epigenetic modifications play significant roles in GD. Ferroptosis and placental dysfunction primarily contribute to intrauterine growth restriction. Conversely, fetal macrosomia arises from maternal hyperglycemia and subsequent fetal hyperinsulinemia, resulting in excessive fetal growth. The chronic inflammatory state and oxidative stress associated with GD exacerbate these complications, creating a hostile intrauterine environment. GD's complex pathophysiology involves multiple disruptions in insulin signaling, mitochondrial function, inflammation, and oxidative stress. Effective management requires early detection, preventive strategies, and international collaboration to standardize care and improve outcomes for mothers and babies.

Keywords: chronic inflammation; gestational diabetes; insulin resistance; mitochondrial dysfunction; oxidative stress; placental dysfunction.

Figure 1

Insulin signaling pathway in normal and gestational diabetes (GD) conditions. (A) Normal insulin signaling. When insulin binds to its receptor, it triggers autophosphorylation on specific tyrosine residues, which creates docking sites for insulin receptor substrates (IRS-1/2). These substrates undergo tyrosine phosphorylation, activating the PI3K pathway. The active PI3K converts PIP2 into PIP3, which recruits and activates Akt at the cell membrane. Activated Akt then facilitates the translocation of GLUT4 vesicles to the cell membrane, allowing glucose uptake into the cell and reducing blood glucose levels. (B) Disrupted insulin signaling in GD. In gestational diabetes, elevated levels of hormones (e.g., human placental lactogen, cortisol) and pro-inflammatory cytokines (e.g., TNF-α, IL-6) induce aberrant serine phosphorylation of IRS-1/2 instead of tyrosine phosphorylation. This modification inhibits IRS function, leading to reduced activation of PI3K. Consequently, the conversion of PIP2 to PIP3 is impaired, decreasing Akt activation. The insufficient activation of Akt prevents GLUT4 vesicles from translocating to the cell membrane, thereby blocking glucose uptake. As a result, glucose remains in the bloodstream, contributing to insulin resistance and hyperglycemia typical of GD.

Figure 2

Molecular and hormonal pathways contributing to insulin resistance in gestational diabetes. (A) Produced by the placenta, Human Placental Lactogen (hPL) levels increase during pregnancy, promoting lipolysis and reducing maternal glucose uptake by inhibiting insulin action. This ensures glucose availability for the fetus but also contributes to insulin resistance by inducing serine phosphorylation of IRS-1, disrupting downstream signaling pathways essential for glucose uptake. (B) Elevated cortisol levels in GD enhance gluconeogenesis and lipolysis, increasing blood glucose and free fatty acids. These free fatty acids activate Protein Kinase C (PKC), which further promotes serine phosphorylation of IRS-1, exacerbating insulin resistance. (C) Dysfunctional mitochondria in GD produce excess reactive oxygen species (ROS), leading to oxidative stress. This oxidative damage further impairs insulin signaling by promoting aberrant serine phosphorylation of IRS-1, contributing to metabolic disturbances. (D) Cytokines such as TNF-α, IL-6, IL-18, and leptin, secreted by adipocytes and immune cells, activate stress kinases (JNK and IKK). These kinases further inhibit insulin signaling by promoting serine phosphorylation of IRS-1, linking chronic inflammation with impaired glucose uptake. (E) Overactivation of the mTOR pathway in GD, partly due to reduced adiponectin levels, leads to increased serine phosphorylation of IRS-1, disrupting insulin signaling. This pathway also impacts cellular growth and autophagy, exacerbating metabolic dysregulation. (F) Klotho, a protein overexpressed in trophoblastic cells in GD, interferes with normal insulin signaling by promoting serine phosphorylation of IRS-1. This disruption reduces PI3K and Akt activation, impairing glucose uptake and contributing to hyperglycemia.

Figure 3

Gut microbiota dysbiosis and its role in metabolic regulation and insulin resistance in gestational diabetes (GD). (A) Dysbiosis leads to reduced production of short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate. These SCFAs, produced through microbial fermentation of dietary fibers, interact with G-protein-coupled receptors (GPCRs) and free fatty acid receptors (FFARs) to regulate gene expression linked to glucose metabolism and inflammation. Reduced SCFA levels impair insulin sensitivity and contribute to systemic inflammation, exacerbating GD. (B) Dysbiosis increases the production of lipopolysaccharides (LPS) from Gram-negative bacteria, which enter the bloodstream and trigger systemic inflammation. This inflammatory response worsens insulin resistance, a hallmark of GD, through activation of inflammatory cytokines. (C) SCFAs also influence epigenetic modifications, including DNA methylation and histone acetylation. These processes regulate the expression of genes involved in glucose metabolism and inflammation. For example, butyrate inhibits histone deacetylases (HDACs), promoting histone acetylation, which enhances the transcription of genes that improve insulin sensitivity and reduce inflammation. SCFAs can also modulate DNA methylation through their impact on DNA methyltransferases (DNMTs), affecting gene activity critical for metabolic regulation in GD.

Figure 4

Mechanisms of ferroptosis and its role in insulin resistance in gestational diabetes (GD). (A) Free iron (Fe²⁺), resulting from the transport of Fe³⁺ by transferrin, catalyzes the Fenton reaction, which produces reactive oxygen species (ROS). These ROS lead to the peroxidation of lipids, primarily polyunsaturated fatty acids, in the cell membrane. (B) Lipid peroxides (Lipid ROS) form as a result of oxidative stress, damaging the cell membrane and triggering ferroptosis. This process is accelerated in GD due to increased oxidative stress. (C) The SLC7A11 (xCT) transport system imports cystine, which is necessary for the synthesis of glutathione (GSH). Glutathione peroxidase 4 (GPX4) uses GSH to neutralize lipid peroxides, preventing ferroptosis. A deficiency or inhibition of this system increases susceptibility to ferroptosis. ACSL4 and LPCAT3 facilitate the incorporation of polyunsaturated fatty acids into membrane phospholipids, making them substrates for lipid peroxidation. NRF2 activation increases the expression of antioxidant genes, protecting cells from ferroptosis. (D) Changes in DNA methylation and histone acetylation influence the expression of key ferroptosis-related genes. For example, histone acetylation at antioxidant gene promoters enhances their expression, providing protection against oxidative stress. However, in GD, these epigenetic modifications can lead to decreased expression of protective genes like GPX4. (E) The accumulation of lipid ROS and the failure of antioxidant systems lead to ferroptosis, resulting in cell death. Dying cells release damage-associated molecular patterns (DAMPs), perpetuating inflammation and contributing to the chronic inflammatory state characteristic of GD.