Placental NLRP3 inflammasome signaling in gestational diabetes and the therapeutic potential of metformin

Gestational diabetes mellitus (GDM) is an obstetric complication affecting up to 20% of pregnancies, and its prevalence is set to increase due to the global rise in maternal obesity. GDM is characterized by maternal insulin resistance, chronic inflammation, and impaired placental function. Epidemiological studies have established that untreated GDM is associated with adverse perinatal outcomes and long-term sequelae for the offspring, including the development of obesity and type 2 diabetes. Nonetheless, the molecular mechanisms underlying the pathophysiology are poorly understood. NLRP3 inflammasome plays ctical role in protective immune functions, however, its excessive activation is associated with chronic inflammation that may result in the development of diabetes (including obesity-induced insulin resistance) or atherosclerosis. Importantly, studies have shown a complex relationship between host lipid metabolism and NLRP3 inflammasome activation. Recently, it has been shown that the placenta expresses high levels of the NLRP3 inflammasome and secretes NLRP3-associated pro-inflammatory cytokines IL-1ß and IL-18. Interestingly, metformin, an alternative first-line agent to insulin in the treatment of GDM, has attracted interest due to its potential to modulate inflammasome activation and affect lipid metabolism. Considering the milieu associated with GDM, our central hypothesis is that GDM promotes a lipotoxic placental environment, leading to hyperactivity of placental NLRP3 inflammasome machinery and contributes to chronic, low-grade inflammation. We speculate that besides antihyperglycemic effect, metformin has additional therapeutic actions by inhibiting NLRP3 inflammasome activation. Understanding these mechanisms is critical for identifying potential lipid biomarkers and novel therapeutic strategies to prevent GDM complications, improve offspring outcomes and decrease the risk of metabolic diseases later in life.

This project recently recieved funding from the Czech Health Research Council (grant no. NU22J-01-00066).