Advances and challenges in the mechanistic understanding of beta-cell dysfunction in gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a metabolic condition of pregnancy, characterized by hyperglycemia and glucose intolerance first diagnosed during the 2nd or 3rd trimester of pregnancy. In healthy pregnancies, pancreatic islets adapt by increasing beta-cell mass and function to maintain glucose homeostasis in the face of systemic insulin resistance, which develops with progression of pregnancy. However, in GDM, individuals experience hyperglycemia when beta-cells fail to compensate for this pregnancy-induced insulin resistance. GDM is a heterogeneous condition, with subtypes characterized by defects in insulin sensitivity, secretion, or both. Despite a substantial number of GDM cases being primarily the result of defects in insulin secretion, the majority of research concerns only insulin sensitivity in peripheral tissues, with less attention paid to insulin secretion and associated islet dysfunction, largely due to the absence of adequate models. Here, we review the pathophysiology of GDM at the islet and beta-cell levels. Numerous factors, including glucotoxicity and proinflammatory cytokines, can contribute to beta-cell dysfunction in GDM, similar to the metabolic dysfunction mechanisms of type 2 diabetes mellitus. Other potential contributors to beta-cell dysfunction in GDM are pregnancy-specific, including dysregulation of placental steroid hormones and lactogenic peptide hormones. Various models have been generated in an attempt to recapitulate the effects of GDM, with the use of modified diets and genetic alterations in animal models common in GDM research. However, there remains no well-characterized physiological animal model of GDM. In vitro models and analysis of human tissues offer promise, but human samples are difficult to access due to the rarity of cadaveric donors for this transient and survivable disease. Defining the molecular and cellular mechanisms driving GDM pathophysiology, specifically at the islet level, is fundamental to developing precise therapeutic strategies that prevent both gestational complications and long-term diabetic sequelae.