Normal human pregnancy is considered a state of enhanced oxidative stress. In pregnancy, it plays important roles in embryo development, implantation, placental development and function, fetal development, and labor. However, pathologic pregnancies, including gestational diabetes mellitus (GDM), are associated with a heightened level of oxidative stress, owing to both overproduction of free radicals and/or a defect in the antioxidant defenses. This has important implications on the mother, placental function, and fetal well-being. Animal models of diabetes have confirmed the important role of oxidative stress in the etiology of congenital malformations; the relative immaturity of the antioxidant system facilitates the exposure of embryos and fetuses to the damaging effects of oxidative stress. Of note, there are only a few clinical studies evaluating the potential beneficial effects of antioxidants in GDM. Thus, whether or not increased antioxidant intake can reduce the complications of GDM in both mother and fetus needs to be explored. This review provides an overview and updated data on our current understanding of the complications associated with oxidative changes in GDM.

The worldwide increase in the incidence of diabetes, the increase in type 2 diabetes in women at reproductive ages, and the cross-generation of the intrauterine programming of type 2 diabetes are the bases for the growing interest in the use of experimental diabetic models in order to gain insight into the mechanisms of induction of developmental alterations in maternal diabetes. In this scenario, experimental models that present the most common features of diabetes in pregnancy are highly required. Several important aspects of human diabetic pregnancies such as the increased rates of spontaneous abortions, malformations, fetoplacental impairments, and offspring diseases in later life can be approached by using the appropriate animal models. The purpose of this review is to give a practical and critical guide into the most frequently used experimental models in diabetes and pregnancy, discuss their advantages and limitations, and describe the aspects of diabetes and pregnancy for which these models are thought to be adequate. This review provides a comprehensive view and an extensive analysis of the different models and phenotypes addressed in diabetic animals throughout pregnancy. The review includes an analysis of the surgical, chemical-induced, and genetic experimental models of diabetes and an evaluation of their use to analyze early pregnancy defects, induction of congenital malformations, placental and fetal alterations, and the intrauterine programming of metabolic diseases in the offspring's later life.

Maternal diabetes increases the risk of congenital malformations, placental dysfunction and diseases in both the neonate and the offspring's later life. Oxidative stress has been involved in the etiology of these abnormalities. Matrix metalloproteases (MMPs), involved in multiple developmental pathways, are increased in the fetus and placenta from diabetic experimental models. As oxidants could be involved in the activation of latent MMPs, we investigated a putative relationship between MMPs activities and oxidative stress in the feto-placental unit of diabetic rats at midgestation. We found that H2O2 enhanced and that superoxide dismutase (SOD) reduced MMPs activities in the maternal side of the placenta and in the fetuses from control and diabetic rats. MMPs were not modified by oxidative status in the fetal side of the placenta. Lipid peroxidation was enhanced in the maternal and fetal sides of the placenta and in the fetus from diabetic rats when compared to controls, and gradually decreased from the maternal placental side to the fetus in diabetic animals. The activities of the antioxidant enzymes SOD and catalase were decreased in the maternal placental side, catalase activity was enhanced in the fetal placental side and both enzymes were increased in the fetuses from diabetic rats when compared to controls. Our data demonstrate changes in the oxidative balance and capability of oxidants to upregulate MMPs activity in the feto-placental unit from diabetic rats, a basis to elucidate links between oxidative stress and alterations in the developmental pathways in which MMPs are involved.

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The mammalian target of rapamycin (mTOR) and the eukaryotic initiation factor 2 (eIF2) signaling pathways control protein synthesis in response to nutrient availability. Moreover, mTOR is a positive regulator of placental nutrient transport and is involved in the regulation of fetal growth. We hypothesized that maternal overweight, induced by a diet with high saturated fat content, i) up-regulates placental mTOR activity and nutrient transport, resulting in fetal overgrowth; ii) inhibits phosphorylation of eIF2 at its alpha subunit (eIF2alpha); and iii) leads to placental inflammation. Albino Wistar female rats were fed a control or high-saturated-fat (HF) diet for 7 wk before mating and during pregnancy. At gestational day 21, the HF diet significantly increased maternal and fetal triglyceride, leptin, and insulin (but not glucose) levels and maternal and fetal weights, and placental weights trended to increase. Phosphorylated 4EBP1 (T37/46 and S65) was significantly higher, and phosphorylated rpS6 (S235/236) tended to increase, in the placentas of dams fed an HF diet, indicating an activation of mTOR complex 1 (mTORC1). Phosphorylation of AMPK and eIF2alpha was reduced in the HF diet group compared to the control. The expression and activity of placental nutrient transporters and lipoprotein lipase (LPL), as well as the activation of inflammatory pathways, were not altered by the maternal diet. We conclude that maternal overweight induced by an HF diet stimulates mTORC1 activity and decreases eIF2alpha phosphorylation in rat placentas. We speculate that these changes may up-regulate protein synthesis and contribute to placental and fetal overgrowth.

Aims To address the effect of a diet enriched in extra virgin olive oil (EVOO) on maternal metabolic parameters and placental proinflammatory markers in Gestational diabetes mellitus (GDM) patients. Methods Pregnant women at 24‐28 weeks of gestation were enrolled: 33 GDM patients which were randomly assigned or not to the EVOO‐enriched group and 17 healthy controls. Metabolic parameters were determined. Peroxisome proliferator activated receptor (PPAR) γ and PPARα protein expression, expression of microRNA (miR)‐130a and miR‐518d (which respectively target these PPAR isoforms) and levels of proinflammatory markers were evaluated in term placentas. Matrix metalloproteinases (MMPs) activity was evaluated in term placentas and umbilical cord blood. Results GDM patients that received the EVOO‐enriched diet showed reduced pregnancy weight gain (GDM‐EVOO:10.3 ± 0.9, GDM:14.2 ± 1.4, P = .03) and reduced triglyceridemia (GDM‐EVOO:231 ± 14, GDM:292 ± 21, P = .02) compared to the non‐EVOO‐enriched GDM group. In GDM placentas, the EVOO‐enriched diet did not regulate PPARγ protein expression or miR‐130a expression, but prevented the reduced PPARα protein expression (P = .02 vs GDM) and the increased miR‐518d expression (P = .009 vs GDM). Increased proinflammatory markers (interleukin‐1β, tumour necrosis factor‐α and nitric oxide overproduction) in GDM placentas were prevented by the EVOO‐enriched diet (respectively P = .001, P = .001 and P = .01 vs GDM). MMPs overactivity was prevented in placenta and umbilical cord blood in the EVOO‐enriched GDM group (MMP‐9: respectively P = .01 and P = .001 vs GDM). Conclusions A diet enriched in EVOO in GDM patients reduced maternal triglyceridemia and weight gain and has antiinflammatory properties in placenta and umbilical cord blood, possibly mediated by the regulation of PPAR pathways.

Leptin has significant effects on appetite, energy expenditure, lipid mobilisation and reproduction. During pregnancy, leptin is produced in the placenta, a tissue in which leptin receptors are highly expressed, suggesting autocrine/paracrine functions for this hormone. In the present study, a putative role of leptin as a regulator of nitric oxide (NO) production and lipid metabolism was evaluated in term human placenta. We demonstrated that leptin enhanced NO production in human placental explants (P < 0.01). Although leptin did not modify the placental levels of cholesteryl esters and phospholipids, leptin decreased levels of triglycerides (P < 0.01) and cholesterol (P < 0.001) in term human placenta. The effect of leptin on lipid mass seems to be independent of the modulation of de novo lipid synthesis because leptin did not modify the incorporation of (14)C-acetate into any of the lipids evaluated. We investigated the effects of leptin on placental lipid catabolism and found that in both term human placental explants and primary cultures of trophoblastic cells, leptin increased glycerol release, an index of the hydrolysis of esterified lipids, in a dose-dependent manner. In conclusion, we have shown that leptin affects NO production and lipid catabolism in human placenta, providing supportive evidence for a role of leptin in placental functions that would determine the transfer of nutrients to the developing fetus.

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