| Part 1 Activity changes of Lp-PLA2 in patients with gestational diabetes and its clinical significanceObjective Analysis of the changes of lipoprotein-associated phospholipase A2(Lp-PLA2)activity and pregnancy outcome in gestational diabetes mellitus(GDM),for exploring the deep mechanisms of inducing the onset and adverse pregnancy outcomes of gestational diabetes.Methods Total 100 pregnant women who underwent routine prenatal examination were admitted to the hospital for delivery in Lianyungang First People’s Hospital from May 2017 to May 2018.They were selected as the study object,among which 52 were in the GDM group and 48 were in the normal control group.Automatic biochemical analyzer was employed to test the biochemical indicators,including fasting plasma glucose(FPG),glycosylated hemoglobin(HbA1c),total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C)and low density lipoprotein cholesterol(LDL-C).The Lp-PLA2 activity was evaluated by enzyme-linked immunosobent assay(ELISA),and the indexes of insulin resistance(HOMA-IR)was calculated by FPG and FINS,HOMA-IR = FPG x FINS/22.5.Changes in peripheral blood Lp-PLA2 activity and biochemical parameters were compared between the two groups.Results1.Comparison of glycolipid metabolism indexes in the two groups: The levelsof FPG、HbA1c、HOMA-IR、TG、TC、LDL-C were significantly increased and HDL-C were significantly decreased in the GDM group when compared with those in the Control group(P <0.05).2.Activity changes of Lp-PLA2 in two groups :The activity of Lp-PLA2 were obviously up-regulated when compared to the Control group.The difference was statistically significant(P < 0.05).3.Correlation analysis of Lp-PLA2 activity with glycolipid metabolism indicators: The activity of Lp-PLA2 was positively correlated with HOMA-RI,TC,and LDL-C(r1=0.393、r2=0.416、r3=0.531,P <0.05).4.Comparison of adverse pregnancy outcomes between the two groups: The incidence of premature rupture of membranes was higher than that in the control group(P < 0.05).The incidences of fetal growth restriction and macrosomia were also higher in the GDM group,but there was no statistical significance between the two groups(P>0.05).Conclusion The serum Lp-PLA2 activity in GDM pregnant women was obviously increased,accompanied by insulin resistance and disorder of blood lipid metabolism,suggesting that Lp-PLA2 may be involved in the occurrence and development of GDM by mediating vascular endothelial function damage,inflammatory changes,regulating blood lipid metabolism and increasing insulin resistance,and further leading to adverse pregnancy outcomes.Part 2 Effects of Lp-PLA2 inhibitor on glucose and lipid metabolism in gestational diabetic ratsObjective To investigate the effect of Lp-PLA2 inhibitor,Darapladib,on glucose and lipid metabolism in gestational diabetic rats induced by streptozotocin(STZ),and to provide theoretical basis for the prevention and treatment of gestational diabetes.Methods The rat models were divided into Control(normal pregnancy),STZ +saline(STZ-induced gestational diabetic rats),STZ + Low-dose and STZ +High-dose darapladib(STZ-induced gestational diabetic rats treated with low/high-dose Darapladib)groups.Pathological changes were observed by Hematoxylin-eosin(HE)and Immunohistochemistry staining.Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay(ELISA).An automatic biochemical analyzer was used to measure the serum levels of biochemical indicators,and homeostatic model assessment for insulin resistance(HOMA-IR)and insulin sensitivity index(ISI)were calculated.Western blot was applied to determine levels of inflammatory cytokines.Results1.Comparison of pregnancy outcomes of rats in each group:Rats in the STZ +saline group were remarkably lower in the weight,fetal weight,number of embryo implantation and live birth number than those in the Control group.However,the Darapladib treatment groups were significantly increased compared with the STZ+saline group,and rats of the STZ + High-dose group increased more obvious(all p <0.05).2.Changes in pancreatic tissue morphology of rats in each group: Compared with the control group,the islets of rats in the STZ+ saline group showed a large number of vacuoles,disordered arrangement and obvious inflammatory cell infiltration;On the other hand,rats in the Darapladib treatment groups had significantly reduced cell vacuoles,a relatively regular morphology and reduced inflammatory cell infiltration.3.Insulin immunohistochemical staining: Rats in STZ+saline group had few insulin positive particles and sparse distributtion;However,in the Darapladib treatment groups,insulin positive particles gradually increased and their distributtion became denser.4.Comparison of glycolipid metabolism indexes of rats in each group: The levels of Lp-PLA2,FPG,HOMA-IR,LDL-C,FFA,TC and TG were significantly up-regulated and ISI,HDL-C were apparently down-regulated in the rats from the STZ + saline group when compared with those in the Control group.On the contrary,rats in the Darapladib treated groups had the reduced levels of Lp-PLA2,FPG,HOMA-IR,LDL-C,FFA,TC and TG,and the elevated level of ISI,HDL-C when compared to the STZ + saline group;and more importantly,the improvement was more obvious in the rats from the STZ + High-dose Darapladib group(all p < 0.05).5.Protein expressions of inflammatory factors in rats of each group:Rats in the STZ + saline group showed substantial up regulations of MCP-1,ICAM-1,IL-6 and TNF-α in the endometrial tissues,as compared to the Control group.In addition,the protein expression levels of MCP-1,ICAM-1,IL-6 and TNF-α were significantly reduced in rats with the Darapladib treatment groups by comparison with the rats from the STZ + saline group.Furthermore,the protein levels in the high-dose group were lower than those in the low-dose group(all P <0.05).Conclusion Lp-PLA2 inhibitor,Darapladib,can promote the endocrine function of pancreatic islets,reduce insulin resistance,enhance insulin sensitivity and improve lipid metabolism disorder in gestational diabetic rats and further improve diverse pregnancy outcomes by regulating inflammatory cytokines,thus providing a new idea for clinical prevention and treatment of gestational diabetes. |
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