ABSTRACT Gestational diabetes mellitus (GDM) is a metabolic condition defined by glucose intolerance during pregnancy, which frequently results in placental malfunction, oxidative stress, and chronic inflammation, all of which are linked to the activation of the NLRP1 inflammasome. GPR39, a G protein‐coupled receptor, has emerged as a possible therapeutic target, and its agonist, TC‐G 1008, may provide protection against metabolic disorders. In this study, we investigated the expression of GPR39 in the murine placenta and its role in GDM‐related placental dysfunction using a high‐fat diet‐induced GDM mouse model. Mice were treated with TC‐G 1008 (7.5 and 15 mg/kg) from gestational day 0 to 18, and placental tissues were analysed via RT‐PCR, Western blot, immunohistochemistry, ELISA, and biochemical assays. Our findings indicated that GPR39 expression was markedly reduced in GDM mice relative to wild‐type controls. Administration of TC‐G 1008 (7.5 and 15 mg/kg) enhanced fetal outcomes, including survival rate, weight, and crown‐rump length, while also mitigating maternal metabolic disorders such as hyperglycaemia, insulin resistance, and dyslipidaemia. Moreover, the administration of TC‐G 1008 mitigated placental oxidative stress by augmenting SOD activity and GSH levels, while inhibiting NLRP1 inflammasome activation, as shown by diminished expression of NLRP1, ASC, and Caspase‐1, alongside lowered levels of IL‐1β and IL‐18. Furthermore, GPR39 activation suppressed the NF‐κB and MAPK signalling pathways. These findings suggest that GPR39 activation by TC‐G 1008 ameliorates placental dysfunction in GDM by mitigating oxidative stress and inflammation via suppression of the NLRP1 inflammasome, highlighting its potential as a therapeutic strategy for GDM‐associated complications.
Zhou et al. (Sat,) studied this question.