Role of macrophages reprogramming in pathogenesis of gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a pregnancy-associated condition resulting from glucose intolerance affecting approximately 14 % of pregnant women worldwide and contributing to both maternal and neonatal complications. Macrophages, essential components of the innate immune system, exist in three main polarization states: M0 (resting), M1 (pro-inflammatory), and M2 (anti-inflammatory). In normal pregnancy, a proper balance between M1 and M2 phenotypes is critical for successful placentation and fetal development. Although this classification provides a useful framework, emerging evidence indicates that macrophages exist along a dynamic continuum of activation states with overlapping functional characteristics rather than discrete polarization categories. Recent studies further reveal that macrophage behavior in pregnancy involves context-dependent and plastic responses that cannot be fully captured by the M1/M2 paradigm alone. However, in GDM, hyperglycaemia significantly influences macrophage reprogramming toward a pro-inflammatory phenotype. The manuscript examines how dysregulated macrophage polarization contributes to insulin resistance, placental dysfunction, and adverse pregnancy outcomes. Emerging evidence suggests that hyperglycaemia induces trained immunity in macrophages, characterized by persistent expression of pro-inflammatory genes. In the GDM placenta, research indicates an altered M1/M2 ratio, though findings vary regarding specific polarization patterns. This review highlights promising therapeutic strategies targeting macrophage repolarization from M1 toward M2 phenotypes, including pharmacological approaches, RNA-based therapies, and ex vivo macrophage manipulation. Understanding macrophage reprogramming in GDM presents novel opportunities for interventions that may improve maternal-fetal outcomes and long-term metabolic health.