Correlation of PI3K p85/p110 alpha and glucose transport proteins in gestational diabetes

Objective Aim of this research is to show the molecular mechanism underlying the formation of gestational diabetes mellitus (GDM), in detail, whether the possible relationship of placental glucose translocation at the receptor and post-receptor level is the same or not in different areas of the placenta. The role of cellular glucose metabolism genes expression levels in the pathogenesis of GDM were investigated by PI3K P85 / p110 alpha and GLUT (1-3-4-12) gene expression, at the receptor and postreceptor levels, respectively. At the same time, the possible relationship between mRNA expression fold change of these molecules and 75 g OGTT blood-glucose levels, which are thought to be responsible for the formation of diabetes, was attempted to be detected in specific area or/and protein groups. Method The samples were collected from volunteering pregnant women with gestational age between 37-42 weeks of pregnancy, who were admitted to Dokuz Eylül University Medical Faculty Hospital Gynecology and Obstetrics Clinic. The placenta tissues obtained from 45 pregnant women were analyzed, of which 25 are part of the Control Group (Group K) as in healthily pregnant without any systemic disease and of which 20 are Gestational Diabetes Mellitus Group (GDM group) as in pregnant women with gestational diabetes. Biopsy specimens from the central and peripheral areas of the maternal and fetal faces of the placenta were preapared in the forms of Maternal Center (MM), Maternal Peripheral (MP), Fetal Center (FM) and Fetal Peripheral (FP). Light microscopic and molecular investigations were performed in all groups in all groups. Sections obtained for light microscopic examination were stained with Hematoxylin & Eosin and Periodic Acid Schift (PAS). General morphology of the placenta and basement membrane thickness were evaluated. Glucose transport proteins for immunohistochemical evaluations were GLUT 1, GLUT 3, GLUT 4 and GLUT 12, TNF sırasıyla, Bcl-2 and Active caspase 3 were stained respectively. In the molecular analysis GLUT 1, GLUT 3, GLUT 4, GLUT 12, PI3K p85 alpha and PI3K p110 alpha expression levels of a total of 6 genes were examined. Control and GDM group 75 g 0GTT 0. hour, 1st hour and 2nd hour blood-glucose levels changes, placental all cases; GLUT 1, GLUT 3, GLUT 4, GLUT 12 gene expression in the Fetal Center (FM), Fetal Peripheral (FP), Maternal Center (MM) and Maternal Peripheral (MP) areas, and also average of the GLUT (1-3-4-12) gen expression, p85 alpha, PI3K p110 alpha and PI3K p85 / p110 alpha mean gene expression levels with blood glucose were compared and statistical analysiss was carried out both within groups and between groups. Result The results of this study indicated that the differences in GLUT and PI3K p85 / p110 alpha gene expressions in different areas of placenta against the acute effects of hyperglycemia increased physiologically in gestational diabetic placentas. In the control group placentas, there is a positive correlation both at the receptor and postreceptor level; while it shifts more to the post-receptor level in gestational diabetic placentas. We concluded that due to the differences in glucose consumption rate and adaptive properties in each area of placenta, GLUT 1 protein acts as primary glucose transporter protein in control group placentas. It worked with both GLUT 4 and GLUT 12 in a correlated manner in insulin response through p110-dependent p85 alpha and p110 alpha complex. However, in gestational diabetic placentas, the ratio between p85 alpha and p110 alpha was impaired and GLUT 4 protein may be involved in the allowing of the passage of glucose in response to insulin. At the same time, GLUT 3 protein can function instead of the GLUT 1 protein which is transporting the primary glucose depending on the glucose concentration in the GDM group. The results of the data evaluated from different areas suggested that the placenta tries to preserve the gene expression levels in the Fetal Peripheral area (FP) but this mechanism is impaired in the maternal surface area, especially at the Maternal Center (MC). These results allow us to explain the cell survival of the placenta through glucose transport and the functional adaptations of gestational diabetic placentas to optimize the fetal growth in the uterus due to low apoptosis and high inflammation in the trophoblast regions. Consequently, we predict that harmful changes in the amount of nutrients provided to the fetus as a result of altered placental phenotype and genotype will have a long-term impact on adult health and morbidity. Furthermore, we suggest, on the basis of previous studies which tried to better explain the role of apoptotic and inflammatory processes in the gestational diabetic placentas, that it may lead to therapeutic approaches to over-induce placenta and fetal growth mechanisms in the pregnant women with GDM. As a conclusion, the comparison of blood glucose concentration levels with placental GLUT and PI3K p85 / p110 alpha gene expression levels revealed distinguishable differences in gene expression levels significantly at 0.hr 100 and above, 1st hour 160 and above and 2nd hour 140 and above (p <0.05). Therefore, it may be possible to contribute to GDM diagnostic criteria levels by supporting with similar studies, by evaluating the relationship between blood glucose concentration and GLUT gene expression levels in particular.