Molecular pathways disrupted by gestational diabetes mellitus

Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for mother and baby. An effective therapeutic that can reduce the incidence of GDM and improve long-term maternal and fetal outcomes is a major research priority, crucially important for public health. A lack of knowledge about the underlying pathophysiology of GDM has hampered the development of such therapeutics. What we do know, however, is that maternal insulin resistance, low-grade inflammation and endothelial cell dysfunction are three central features of pregnancies complicated by GDM. Indeed, data generated over the past decade have implicated a number of candidate regulators of insulin resistance, inflammation and endothelial cell dysfunction in placenta, maternal adipose tissue and skeletal muscle. These include nuclear factor-kappa B (NF-kappa B), peroxisome proliferator-activated receptors (PPARs), sirtuins (SIRTs), 5' AMP-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK3), PI3K/mTOR, inflammasome and endoplasmic reticulum (ER) stress. In this review, the identification of these as key modulators of GDM will be discussed. The biochemical pathways involved in the formation of these may represent potential sites for intervention that may translate to therapeutic interventions to prevent the development of GDM.