{"title":"Kisspeptin-10通过激活环AMP/蛋白激酶A通路抑制胎盘滋养细胞胰岛素抵抗改善妊娠糖尿病大鼠症状","authors":"Jianhua Li, Jinhuan Chen, Lin Lu, Bei Gan","doi":"10.1111/cbdd.70169","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>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 (<i>Gpr54</i>), 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 <i>Gpr54</i> 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 <i>Glut</i>-<i>4</i>, <i>Insr</i>, and <i>Irs1</i> 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.</p>\n </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Jianhua Li, Jinhuan Chen, Lin Lu, Bei Gan\",\"doi\":\"10.1111/cbdd.70169\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>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 (<i>Gpr54</i>), 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 <i>Gpr54</i> 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 <i>Glut</i>-<i>4</i>, <i>Insr</i>, and <i>Irs1</i> 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.</p>\\n </div>\",\"PeriodicalId\":143,\"journal\":{\"name\":\"Chemical Biology & Drug Design\",\"volume\":\"106 3\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Biology & Drug Design\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cbdd.70169\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Biology & Drug Design","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cbdd.70169","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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
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.
期刊介绍:
Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.