Kisspeptin‐10 Improves Gestational Diabetes Mellitus Symptoms in Rats by Suppressing Insulin Resistance in Placental Trophoblast Cells by Activating the Cyclic AMP/Protein Kinase A Pathway

ABSTRACT Gestational diabetes mellitus (GDM) is a common pregnancy complication that leads to insulin resistance (IR) and adversely affects both maternal and fetal health. Kisspeptin‐10 (Kp‐10), a peptide acting via G Protein‐Coupled Receptor 54 ( Gpr54 ), has shown potential in modulating insulin secretion, but its role in GDM remains unclear. This study explores Kp‐10's therapeutic effects on GDM by targeting IR in placental tissues. We used GDM rat models (induced by a high‐fat diet and streptozotocin) and high‐glucose‐treated HTR8/SVneo trophoblast cells to investigate Kp‐10's effects on glucose metabolism, insulin signaling, and the cAMP/PKA pathway. Our results show that Gpr54 expression was significantly downregulated in the placental tissues of GDM rats, which was associated with impaired glucose uptake and IR. Kp‐10 treatment improved fasting blood glucose (FBG) levels, insulin sensitivity, and fetal outcomes, including increased fetal weight and decreased fetal blood glucose. Moreover, Kp‐10 restored the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway and enhanced glucose uptake by upregulating Glut ‐ 4 , Insr , and Irs1 expression in both placental tissues and HTR8/SVneo cells. The effects of Kp‐10 were reversed by the cAMP inhibitor SQ22536, confirming the involvement of the cAMP/PKA pathway in its anti‐IR effects. Our findings suggest that Kp‐10 has the potential as a therapeutic agent for alleviating IR in GDM and improving maternal–fetal outcomes.