25Aim/hypothesis: Placenta of women with gestational diabetes mellitus (GDM) exhibits an 26 altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid 27 metabolism remains obscure. We hypothesized that high-glucose levels reduce mitochondrial fatty 28 acid oxidation (FAO) and increase triglyceride accumulation in human placenta. 29 Methods:To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty 30 acid synthesis, triglyceride levels and carnitine palmitoyltransferase activities (CPT) in placental 31 explants of women with GDM or with no pregnancy complication. 32 Results:In women with GDM, FAO was reduced by ~30% without change in mitochondrial 33 content, and triglyceride content was 3-fold higher than control group. Likewise, in placental 34

ObjectivesOxidative stress and inflammation have been postulated as underlying mechanisms for the development of obesity-related insulin resistance. This association however, remains elusive especially in childhood. We sought to investigate this relation by measuring oxidative stress and antioxidant response biomarkers, before and during an oral glucose tolerance test (OGTT), in different biological samples from obese children.Subjects24 children were recruited for the study, (18 obese and 6 controls). After OGTT, the obese group was subdivided in two, according to whether or not carbohydrate metabolic impairment (Ob.IR+, Ob.IR-; respectively) was found. Different biomarkers were analyzed after fasting (T = 0) and during an OGTT (T = 60 and 120 min). Lipoperoxides were measured in plasma, erythrocytes, and urine; while advanced glycation end products were determined in plasma, and redox status (GSH/GSSG ratio) in erythrocytes.ResultsWe found marked differences in the characterization of the oxidative status in urine and erythrocytes, and in the dynamics of the antioxidant response during OGTT. Specifically, Ob.IR+ children show increased oxidative stress, deficient antioxidant response and a significant imbalance in redox status, in comparison to controls and Ob.IR- children.ConclusionObese children with insulin resistance show increased levels of oxidative stress biomarkers, and a stunted antioxidant response to an OGTT leading to increased oxidative stress after a single glucose load, as detected in erythrocytes, but not in plasma. We propose erythrocytes as sensors of early and acute changes in oxidative stress associated with insulin resistance in childhood obesity. This is a pilot study, performed with a limited sample size, so data should be interpreted with caution until reproduced.

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Placental metabolism is an important mechanism for the regulation of fetal growth and long-term health of the newborns. In this study, we investigated the effects of maternal metabolic environment on human placental fatty acid and glucose metabolism. We used placental explants from uncomplicated pregnancies or pregnancies complicated with gestational diabetes mellitus (GDM), undergoing vaginal delivery (VD) or cesarean section (CS). Fatty acid oxidation (FAO) and glucose uptake (2-DOG) were similar in both modes of delivery in normal and GDM pregnancies. However, placental explants from GDM exhibited 40% to 50% reduced FAO capacity compared to control placentas in women undergoing VD or CS. In contrast, 2-DOG uptake was 2- to 3-fold higher in placental explants from GDM compared to control placentas in women undergoing VD or CS, respectively. In conclusion, ex vivo placental fuel selection is influenced by maternal GDM, but placental metabolic characteristics are not altered by the mode of delivery.

Childhood obesity, and specifically its metabolic complications, are related to deficient antioxidant capacity and oxidative stress. Erythrocytes are constantly exposed to multiple sources of oxidative stress; hence, they are equipped with powerful antioxidant mechanisms requiring permanent reducing power generation and turnover. Glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) are two key enzymes on the pentose phosphate pathway. Both enzymes supply reducing power by generating NADPH, which is essential for maintaining the redox balance within the cell and the activity of other antioxidant enzymes. We hypothesized that obese children with insulin resistance would exhibit blunted G6PDH and 6PGDH activities, contributing to their erythrocytes’ redox status imbalances. We studied 15 control and 24 obese prepubertal children, 12 of whom were insulin-resistant according to an oral glucose tolerance test (OGTT). We analyzed erythroid malondialdehyde (MDA) and carbonyl group levels as oxidative stress markers. NADP+/NADPH and GSH/GSSG were measured to determine redox status, and NADPH production by both G6PDH and 6PGDH was assayed spectrophotometrically to characterize pentose phosphate pathway activity. Finally, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) activities were also assessed. As expected, MDA and carbonyl groups levels were higher at baseline and along the OGTT in insulin-resistant children. Both redox indicators showed an imbalance in favor of the oxidized forms along the OGTT in the insulin-resistant obese group. Additionally, the NADPH synthesis, as well as GR activity, were decreased. H2O2 removing enzyme activities were depleted at baseline in both obese groups, although after sugar intake only metabolically healthy obese participants were able to maintain their catalase activity. No change was detected in SOD activity between groups. Our results show that obese children with insulin resistance present higher levels of oxidative damage, blunted capacity to generate reducing power, and hampered function of key NADPH-dependent antioxidant enzymes.