Elisa Keating

Impact of Gestational Diabetes Mellitus in the Maternal-to-Fetal Transport of Nutrients

Gestational diabetes mellitus (GDM) is a metabolic disorder prevalent among pregnant women. This disease increases the risk of adverse perinatal outcomes and diseases in the offspring later in life. The human placenta, the main interface between the maternal and fetal blood circulations, is responsible for the maternal-to-fetal transfer of nutrients essential for fetal growth and development. In this context, the aim of this article is to review the latest advances in the placental transport of macro and micronutrients and how they are affected by GDM and its associated conditions, such as elevated levels of glucose, insulin, leptin, inflammation, and oxidative stress. Data analyzed in this article suggest that GDM and its associated conditions, particularly high levels of glucose, leptin, and oxidative stress, disturb placental nutrient transport and, consequently, fetal nutrient supply. As a consequence, this disturbance may contribute to the fetal and postnatal adverse health outcomes associated with GDM.

Folates and aging: Role in mild cognitive impairment, dementia and depression

In almost all tissues, including the brain, folates are required for one-carbon transfer reactions, which are essential for the synthesis of DNA and RNA nucleotides, the metabolism of amino acids and the occurrence of methylation reactions. The aim of this paper is to review the impact of folate status on the risk of development of neuropsychiatric disorders in older individuals. The prevalence of folate deficiency is high among individuals aged ≥ 65 years mainly due to reduced dietary intake and intestinal malabsorption. Population-based studies have demonstrated that a low folate status is associated with mild cognitive impairment, dementia (particularly Alzheimers disease) and depression in healthy and neuropsychiatric diseased older individuals. The proposed mechanisms underlying that association include hyperhomocysteinemia, lower methylation reactions and tetrahydrobiopterin levels, and excessive misincorporation of uracil into DNA. However, currently, there is no consistent evidence demonstrating that folic acid supplementation improves cognitive function or slows cognitive decline in healthy or cognitively impaired older individuals. In conclusion, folate deficiency seems to be an important contributor for the onset and progression of neuropsychiatric diseases in the geriatric population but additional studies are needed in order to increase the knowledge of this promising, but still largely unexplored, area of research.

Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism.

In this study we characterized (3)H-2-deoxy-d-glucose ((3)H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon (3)H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells (3)H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (Vmax) and affinity (Km), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that (3)H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited (3)H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors.

Folic acid uptake by the human syncytiotrophoblast: Interference by pharmacotherapy, drugs of abuse and pathological conditions

Folic acid (FA) is crucial for fetal development. We aimed to study the modulation of FA placental uptake by: hyperserotoninemia and hyperglycaemia, anti-hypertensives, insulin and drugs of abuse. For this, we characterized (3)H-FA uptake by primary cultures of human cytotrophoblasts (TB cells) and tested the effects of these compounds upon (3)H-FA uptake, TB cell viability and gene expression. Our results show that: (a) acutely, (3)H-FA uptake was decreased by labetalol (0.1-1000 microM), ecstasy and amphetamine (0.025-25 microM); and (b) chronically, (3)H-FA uptake was decreased by high glucose (30 mM), atenolol, nicotine (0.1 and 10 microM), ethanol (0.01 and 10mM), ecstasy, amphetamine (0.25 and 1 microM) and tetrahydrocannabinol (1 and 100 nM). Moreover, many of these drugs were cytotoxic and they differentially modulated the mRNA expression of FA placental transport systems. Our results suggest that inhibition of FA placental uptake may constitute one of the mechanisms involved in the fetotoxicity of many of the compounds tested.

Gestational diabetes mellitus decreases placental uptake of long-chain polyunsaturated fatty acids: involvement of long-chain acyl-CoA synthetase

The long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic (AA) and docosahexaenoic (DHA) acids are essential for fetal development. Gestational diabetes mellitus (GDM) is a pregnancy disorder associated with perinatal and lifelong risk complications for both the mother and the newborn. Our aim was to investigate the influence of GDM, and some of its associated conditions, upon the placental uptake of AA and DHA. Uptake of (14)C-AA and (14)C-DHA by human trophoblasts obtained from normal pregnancies (NTB cells) was mediated by both saturable (for lower substrate concentrations) and non-saturable (for higher substrate concentrations) mechanisms. Uptake of both fatty acids was inhibited by other LC-PUFAs and, markedly, by the long-chain acyl-CoA synthetase (ACSL) inhibitor, triacsin C. Human trophoblasts obtained from GDM pregnancies (DTB cells) showed a significantly lower (14)C-AA and (14)C-DHA accumulation, through a decrease in both the saturable and the non-saturable components of uptake, which was associated with a decrease in ACSL1 mRNA levels. Uptake of LC-PUFAs by NTB cells increased (by 20-25%) after short-term exposure to TNF-α ((14)C-AA and (14)C-DHA) and insulin ((14)C-DHA). In conclusion, GDM, distinctly from its associated conditions, markedly decreases placental uptake of LC-PUFAs, which probably contributes to the deleterious effects of this disease for the newborn.

The Chemopreventive Effect of the Dietary Compound Kaempferol on the MCF-7 Human Breast Cancer Cell Line Is Dependent on Inhibition of Glucose Cellular Uptake

Our aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of 3H-deoxy-D-glucose (3H-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26 min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10–100 µM) inhibited 3H-DG uptake. Kaempferol was found to be the most potent inhibitor of 3H-DG uptake [IC50 of 4 µM (1.6–9.8)], behaving as a mixed-type inhibitor. In the long-term (24 h), kaempferol (30 µM) was also able to inhibit 3H-DG uptake, associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 µM) revealed antiproliferative (sulforhodamine B and 3H-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1 mM) glucose conditions and reversed by high extracellular (20 mM) glucose conditions. Finally, exposure of cells to kaempferol (30 µM) induced an increase in extracellular lactate levels over time (to 731 ± 32% of control after a 24 h exposure), due to inhibition of MCT1-mediated lactate cellular uptake. In conclusion, kaempferol potently inhibits glucose uptake by MCF-7 cells, apparently by decreasing GLUT1-mediated glucose uptake. The antiproliferative and cytotoxic effect of kaempferol in these cells appears to be dependent on this effect.

Exposure to non-nutritive sweeteners during pregnancy and lactation: Impact in programming of metabolic diseases in the progeny later in life

The nutritional environment during embryonic, fetal and neonatal development plays a crucial role in the offsprings risk of developing diseases later in life. Although non-nutritive sweeteners (NNS) provide sweet taste without contributing to energy intake, animal studies showed that long-term consumption of NSS, particularly aspartame, starting during the perigestational period may predispose the offspring to develop obesity and metabolic syndrome later in life. In this paper, we review the impact of NNS exposure during the perigestational period on the long-term disease risk of the offspring, with a particular focus on metabolic diseases. Some mechanisms underlying NNS adverse metabolic effects have been proposed, such as an increase in intestinal glucose absorption, alterations in intestinal microbiota, induction of oxidative stress and a dysregulation of appetite and reward responses. The data reviewed herein suggest that NNS consumption by pregnant and lactating women should be looked with particular caution and requires further research.

Folic acid uptake by the human syncytiotrophoblast is affected by gestational diabetes, hyperleptinemia, and TNF-α

Background:The mechanisms whereby gestational diabetes mellitus (GDM) increases the risk of fetal overgrowth and development of metabolic diseases later in life are likely to involve changes in nutrient supply to the fetus. Hence, in this work, we hypothesize that GDM may affect folic acid (FA) supply to the placenta and fetus.Methods:We compared 3H-FA uptake by human cytotrophoblasts isolated from normal pregnancies (normal trophoblasts; NTB cells) and GDM pregnancies (diabetic trophoblasts; DTB cells) and investigated the effect of GDM hallmarks on 3H-FA uptake by BeWo cells.Results:3H-FA uptake by NTB and DTB cells was time dependent and acidic pH stimulated. When compared with NTB, 3H-FA uptake by DTB cells was more sensitive to acidic pH changes and to 5-methyltetrahydrofolate and pemetrexed (PTX) inhibition, indicating a proportionally greater involvement of the proton-coupled folate transporter (PCFT). A 4-h exposure of BeWo cells to lipopolysaccharide (LPS, 1–10 μg/ml) or to high levels of tumor necrosis factor-α (TNF-α, 300 ng/l) significantly reduced 3H-FA uptake. Moreover, hyperleptinemic conditions (100 ng/ml leptin) decreased 3H-FA uptake by BeWo cells in a time-dependent manner when compared with normoleptinemic conditions (1 ng/ml leptin).Conclusion:GDM modulates 3H-FA uptake by the syncytiotrophoblast, and leptin as well as TNF-α downregulate it.

Maternal Undernutrition and Fetal Developmental Programming of Obesity: The Glucocorticoid Connection

An adequate maternal nutrition during pregnancy is crucial for the health outcome of offspring in adulthood. Maternal undernutrition during critical periods of fetal development can program the fetus for metabolic syndrome (MetS) later in life, especially when postnatally challenged with a hypernutritive diet. Adipogenesis, which begins in utero and accelerates in neonatal life, is a major candidate for developmental programming. During fetal development, the hypothalamic–pituitary–adrenal (HPA) axis is extremely susceptible to programming, and the HPA tone is increased throughout life in undernourished conditions. As a consequence, an alteration in the expression and function of glucocorticoid (GC) receptors and of the major GC regulatory enzymes (11β-hydroxysteroid dehydrogenase 1 and -2) occurs. In this review, we will give insights into the role of maternoplacental adverse interactions under the specific context of maternal undernutrition, for later-in-life MetS development, with a special emphasis on the role of GCs.

Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life

The aim of this study was to understand whether high folic acid (HFA) exposure during the perigestational period induces metabolic dysfunction in the offspring, later in life. To do this, female Sprague-Dawley rats (G0) were administered a dose of folic acid (FA) recommended for pregnancy (control, C, 2 mg FA/kg of diet, n=5) or a high dose of FA (HFA, 40 mg FA/kg of diet, n=5). Supplementation began at mating and lasted throughout pregnancy and lactation. Body weight and food and fluid intake were monitored in G0 and their offspring (G1) till G1 were 13 months of age. Metabolic blood profiles were assessed in G1 at 3 and 13 months of age (3M and 13M respectively). Both G0 and G1 HFA females had increased body weight gain when compared with controls, particularly 22 (G0) and 10 (G1) weeks after FA supplementation had been stopped. G1 female offspring of HFA mothers had increased glycemia at 3M, and both female and male G1 offspring of HFA mothers had decreased glucose tolerance at 13M, when compared with matched controls. At 13M, G1 female offspring of HFA mothers had increased insulin and decreased adiponectin levels, and G1 male offspring of HFA mothers had increased levels of leptin, when compared with matched controls. In addition, feeding of fructose to adult offspring revealed that perigestational exposure to HFA renders female progeny more susceptible to developing metabolic unbalance upon such a challenge. The results of this work indicate that perigestational HFA exposure the affects long-term metabolic phenotype of the offspring, predisposing them to an insulin-resistant state.