Efecto del tratamiento de la diabetes gestacional en el transporte placentario de nutrientes al feto

Resumo

Summary: The incidence of Gestational Diabetes Mellitus (GDM) has been increasing in the last few years due to the exponential rise in obsesity levels wordlwide. The GDM increases the risk of fetal macrosomia and adiposity in newborn babies, which increases the probability of them becoming obese later in life. Moreover, GDM produces an alteration in the structure and the metabolism of the placenta and it would be of great interest to understand how the mechanisms for the transfer of nutrients to the fetus are affected and to learn how to improve the diet or insulin treatment in these patients. The main objective of this doctoral thesis, through in vivo and in vitro studies, was to understand the effect of GDM treatment on the expression of fatty acid transporters and on the activation of the main insulin signalling pathways in the placenta. The selectived mechanisms of the 3 omega fatty acid transference to the fetus and their possible alteration in GDM pregnancies were also investigated. These alterations may affect neuro development in children. Pregnant women (28-32 weeks gestation) were enrolled at the Gynaecology Department at the Virgen de la Arrixaca Hospital in Murcia: 25 pregnant women controls, 23 diet-treated GDM , and 20 insulin-treated GDM. Blood samples for biochemical measurements and analysis of lipids and amino acids were taken at the time the women were enrolled and at the time of delivery. Samples of cord blood and placenta were also taken in the birth for Western blot analysis of placental fatty acid transporters (LPL, EL, FATP-1,, FATP-4, A-FABP, FAT and MFSD2A), and of phosphorylated molecular mediators of insulin signalling pathways (p-Akt, p-ERK, p-S6, IRS1/p-2). A placenta tumor cell line (BeWo) was in vitro stimulated with inhibitors of the insulin signaling pathway (PI3K-Akt, ERK) in order to study the effect that insulin could have on lipid transporters. Children of women with insulin treated GDM had more fetal adiposity than those of mothers controls.Levels of fatty acids transporters (FAT, FATP-1 and A-FABP) tended to increase in the placentas of diabetic women, the highest values being in those treated with insulin. However, MFSD2A levels were lower in both groups of diabetic women, which coincides with the lower levels of the omega 3 Docosahexaenoic acid (DHA) in these children. The activation levels of Akt and ERK were significantly higher in the placentas of the diabetic women treated with insulin, and they were associated with the levels of the lipid transporters FAT and A-FABP, suggesting that insulin plays a very important role in the regulation of the transport of lipids. In BeWo cells, lipid transporter levels fell drastically when they were treated with inhibitors of the insulin routes. This fact corroborated our in vivo results in regards to the role played by the insulin in the regulation of these transporters. At the time of enrollment, maternal levels of glucose and insulin were associated with an increase of the placenta insulin pathway at the time of delivery. This consequently led to increases in both the placenta weight and in the fatty acid transporters in general, but not on the DHA transporter. This increase allowed a greater fat transfer from the mother to the fetus that promoted the fetal adiposity. Thus, it would be necessary to begin the insulin treatment of patients with GDM earlier than is currently done in order to better control the maternal blood glucose, and to reduce placental alterations and the consequent risk of obesity in children.