The Role Of Endoplasmic Reticulum Stress Apoptosis Pathway TRAF2 And Caspase3 In The Pathogenesis Of Gestational Diabetes Mellitus

1 Background and ObjectivesIn recent years, the rising incidence of GDM led to serious economic and public health problem. The intrauterine environment of high glucose in pregnant women with GDM not only increased the risk of macrosomia, congenital malformations, preterm birth, stillbirth, and cesarean delivery, but also increased the risk of neonatal hypoglycemia, red blood cells increased disease, high blood bilirubin and other perinatal complications. At the same time, it increased the risk of obesity, type 2 diabetes and cardiovascular disease of the future generations. Studies have shown that the islet beta cells apoptosis induced by endoplasmic reticulum stress(ERS) take part in the occurrence and development of various types of diabetes, but its role in the pathogenesis of GDM had little research. We need further study.This study treated the 24 to 28 weeks pregnancy women who were first found abnormal glucose tolerance as the research object. The mRNA expression of TRAF2 and Caspase3, which are two signal molecules of ERS apoptosis pathway, in their peripheral blood mononuclear cell(PBMC) were measured to analysis the role of TRAF2 and Caspase3 in the pathogenesis of gestational diabetes mellitus. 2 Subjects and MethodsThe 24 to 28 weeks pregnancy women between 25 and 35 years old,according to the 75 g glucose tolerance test(OGTT), were divided into 64 cases of gestational diabetes mellitus(GDM) group and 60 cases of normal glucose tolerance(NGT) group. 30 cases of the same age non pregnant women were chosen as the negative control group. All subjects were single fetal pregnant and there was no history of chronic diseases such as diabetes and high blood pressure, no polycystic ovary syndrome, no severe rheumatic autoimmune disease, no kidney disease and thyroid disease, no recent infections and stress, and so on.All subjects overnight fasting 8 to 10 hours come to maternity clinic of our hospital on an empty stomach at 8:00 am. The general clinical indicators, the body mass index(BMI), blood glucose, insulin of OGTT 0, 60, 120 minutes, blood fat, glycosylated hemoglobin and routine blood were measured and record. The steady state model assessment of insulin resistance index(HOMA-IR), islet beta cell function index(HOMA-HBCI) and insulin secretion index(△I60/△G60) were calculated. TRAF2 and Caspase3 mRNA expression were detected using real-time fluorescent quantitative PCR method. 3 Results3.1 The general situation: compared with normal control group, PG2 h, INS2 h in NGT group was obviously increased(P<0.05), FINS, Ln(IR) in GDM group increased significantly(P<0.05), TG, TC, HDL-C, LDL-C in GDM group and NGT group were significantly increased(P<0.05), while, hemoglobin, PBMC were significantly decreased(P<0.05). In addition, in GDM group, HbA1 C, FPG, PG1 h, PG2 h, INS1 h and INS2 h were significantly higher than the control group and NGT group(P<0.05), while Ln(HBCI), Ln(△I60/△G60) were significantly decreased(P<0.05).3.2 The TRAF2 and Caspase3 mRNA expression: In NGT group, the expression level of Caspase3 mRNA significantly increased compared with control group(P<0.05), while the expression level of TRAF2 mRNA have increased, but no significant difference(P>0.05); In GDM group, the expression level of TRAF2, Caspase3 mRNA were significantly increased compared with the control group and NGT group(P<0.05).3.3 Statistical analysis:(1) The linear correlation analysis: the Caspase3 mRNA in PBMC was significantly positive correlate to the increased BMI during pregnancy, HbA1 C, TG, TC, HDL-C, PG1 h, PG2 h, INS1 h, INS2 h, TRAF2(r=0.442, r=0.442, r=0.485, r=0.314, r=0.176, r=0.454, r=0.610, r=0.344, r=0.516, r=0.788, P<0.05), while it was significantly negative correlate to the hemoglobin, concentration of PBMC, Ln(HBCI), Ln(△I60/△G60)(r=0.389, r=0.389, r=0.184, r=0.234, P<0.05);(2) Multiple linear stepwise regression analysis; TRAF2, the increased BMI during pregnancy, TG were independent factors that affected the expression level of Caspase3 mRNA(r=0.696, r=0.696, r=0.297, P<0.05), the regression equation is: Y=0.696 x TRAF2 + 0.239 x the increased BMI during pregnancy + 0.297 x TG;(3)Binary Logistic regression analysis: the expression level of Caspase3 mRNA and TRAF2 mRNA correlated with the onset of GDM(Caspase3 mRNA: OR 5.704,95% CI 1.118~29.102;TRAF2 mRNA: OR 78.826,95% CI 7.526~825.637). 4 Conclusions1. IR and the defects of islet beta cells function existed in patients with GDM and the ERS reaction was enhanced in their body. ERS might promote the development of GDM by activating Caspase apoptosis passway.2. TRAF2, the increased BMI during pregnancy and TG were independent factors that affected the expression level of Caspase3 mRNA. The increased BMI during pregnancy and TG may involve in the pathogenesis of GDM through ERS passway.