Influences Of Different Glucose Metabolic Status And Islet β Cell Function Heterogeneity In Pregnancy On Perinatal Outcomes And Mechenisms Of Activating TGR5 To Regulate The Gestational Glucose Metabolism

Aims The association between maternal metabolism and.perinatal outcomes has been attached the great importance.This research mainly focused on three themes: first,it assessed the relationship between levels of alkaline phosphatase(ALP)in early pregnancy and the incidence of large-for-gestational-age(LGA)neonates;Moreover,it investigated whether the heterogeneity of insulin resistance and beta cell dysfunction in gestational diabetes mellitus(GDM)have different impacts on perinatal negative outcomes;Besides,it have further explored a new and subtle mechanism to improve glucose homeostasis during pregnancy througth the activation of Takeda G protein-coupled receptor 5(TGR5)in macrophages to impact their the migration and polarization.Methods A prospective of pregnant women cohort was built up.The biochemical characters were measured from pregnant women at 13-16 th weeks of gestation.All subjects underwent a diagnostic 75-g oral glucose tolerance test at 24–28th weeks of gestation and perinatal outcomes were recorded at delivery.The relationship between biochemical features and perinatal outcomes were analyzed in 214 pregnant women with normal glucose tolerance.Then according to the hetergenosity of GDM,206 pregnant women with GDM were classified into three groups: GDM-resistance(n=35),GDM-dysfunction(n=43)and GDM-mix(n=79).Differences in perinatal outcomes among these groups were identified.In basic research,we extracted and induced bone marrow derived macrophages(BMDM)in GDM model mouse andinvestigate impacts of acvating TGR5 in polarization and migration.The real-time PCR was performed to evaluate pro-inflamation genes expression and levels of pro-inflamation and chemokine ligands in supernatants were tested by cytometric bead array and ELISA.The performance of BMDM migration was measured by Transwell assay.After the activation of TGR5,the activity of proprotein convertase 1/3 was assessed by Western blot.Results Women diagnosed as LGA(n = 23)held higher level of ALP than women in non-LGA group(n = 191)(48± 14 vs 42 ±11;P=0.008).Logistic regression analysis revealed high concertrations of ALP was an independent risk factor for LGA after adjustment for confounding factors(OR,1.05;95% CI,1.00-1.11,P=0.04).Women with combination in insulin resistance and beta cell dysfunction were more likely to be subjected to LGA(P= 0.008)and adverse perinatal outcomes(P= 0.005),although these diferences were normalized after adjusting prepregnancy BMI and other comfounders.In basic research,we found that pro-inflamation such as IL-1β,IL-6 and TNF-α and chemokine genes such as CCL2,CCL4,CCL5 and CCL7 expression was inhibited(All P < 0.01 and all P < 0.05,respectively)and levels of pro-inflamation including IL-1β,IL-6 and TNF-α and chemokine ligands such as CCL2,CCL3 and CCL4 in supernatants also decreased after the activation of TGR5 in BMDM,compared with BMDM treated with lipopolysaccharides(LPS).(All P < 0.05 and all P < 0.001,respectively).The migration of BMDM was also inhibited in TGR5 activation group,compared with blank control group(P < 0.001).Finally,the increasing expression in TGR5 activation group was observed compared with BMDM with LPS treated.Conclusions Early elevated ALP level in pregnace was independently associated with LGA.It can be a potential biomarker to predict the occurrence of LGA at early pregnancy.Futhermore,the heterogeneity of insulin resistance and beta cell dysfunction was associtated with diverse adverse perinatal outcomes in women with GDM.Moreover,Activation of TGR5 inhibited the polarization to M1 and the chemokine ligand genes expression in BMDM,which may be attributed to the upregulating pathway of PC1/3.