his in turn increases IR internalization and insulin resistance. The 14-3-3 proteins are also involved in the insulin signal pathway. Upon stimulation by insulin, the insulin receptor phosphorylates tyrosine residues in insulin receptor substrate-1 and subsequently, phosphorylated IRS-1 associates with phosphoinositol-3-kinase. 14-3-3 proteins can bind IRS-1 and thus inhibit insulin signaling in several ways. Firstly, 14-3-3 proteins compete with IR for IRS binding. Secondly, the association of 14-3-3 proteins and IRS decreases PI3K activity. Thirdly, binding of the 14-3-3 protein to the IRS-1/PI3K complex, can result in translocation of the complex to the cytosol, thereby impeding the pathway. It is clear from these previous studies that 14-3-3 proteins play an essential role in insulin desensitization and therefore may be associated with insulin resistance induced by a chronic hyperglucose and hyperinsulin milieu. It is therefore likely that up-regulation of this complex in the GDM placenta villi is directly related to hyperinsulinemia in GDM mothers. Combining the alterations in expression of Annexin A2 and 143-3 complex, we speculate that GDM placental cells make adjustments in response to chronic insulin stimulation by downregulating insulin receptors and blocking the insulin signal pathway, thereby reducing the uptake of glucose. TMS web hyperglycemia and hyperinsulinemia are two major pathophysiological changes in GDM. Maternal hyperglycemia is able to induce fetal hyperglycemia due to an increased transplacental transfer of glucose, while maternal insulin is not 
able to cross the placenta. Fetal hyperglycemia can stimulate insulin secretion by the fetal pancreas, subsequently leading to normalization of fetal glycemia. However, intrauterine hyperglycemia and hyperinsulinemia are also associated with macrosomia in GDM pregnancy, by a mechanism known as the Pederson hypothesis, the pivotal step of which is the transplacental transportation of high levels of glucose. Although the expression of insulin-sensitive GLUT4 on term placenta is low, our finding of the downregulated insulin signal pathway and putative decreased glucose uptake of placenta villi may still have a potential biological significance in the control of transplacental transportation of glucose, and therefore is important in the counteraction of intrauterine hyperglycemia, hyperinsulinemia and macrosomia in GDM pregnancy. Proteins found to have altered expression between GDM and NGT placental groups in the present study are associated with additional cellular functions including coagulation and fibrinolysis balance. A hypercoagulable state becomes more common during pregnancy, especially in those complicated with GDM. However, we found Annexin A5, a major protein involved in hypocoagulation, was up-regulated in GDM placenta villi. Annexin A5, otherwise known as placenta anticoagulant protein 1, can form a shield around negatively-charged phospholipid molecules and inhibit blood coagulation. The anti-coagulation effects of Annexin A5 includes competing with activated factor VIII for phosphatidylserine binding sites, inhibiting thromboplastin and blocking the binding of factor X to thrombinstimulated platelets . Therefore, the placenta may up-regulate and secrete more Annexin A5 in order to counteract the hypercoagulation state induced by GDM. The present finding of Ras related protein Rap1A down-regulation may be associated with the diminished fibrinolytic activity in these G