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- Author: Martha Lappas x
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Obstetrics, Mercy Perinatal Research Centre, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia
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Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). The aim of this study was to determine whether levels of NOD1 and NOD2 are increased in adipose tissue of women with GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance (NGT). In both omental and subcutaneous adipose tissues from NGT and GDM women, the NOD1 ligand g-d-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesion molecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFκB, as the NFκB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion of pro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM.
Mercy Perinatal Research Centre, Translational Proteomics, Department of Obstetrics and Gynaecology
Mercy Perinatal Research Centre, Translational Proteomics, Department of Obstetrics and Gynaecology
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Mercy Perinatal Research Centre, Translational Proteomics, Department of Obstetrics and Gynaecology
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Mercy Perinatal Research Centre, Translational Proteomics, Department of Obstetrics and Gynaecology
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In response to oxidative stress, gestational diabetes mellitus (GDM) placenta releases less 8-isoprostane and tumour necrosis factor (TNF) α. The effect of oxidative stress on other cytokines and antioxidant gene expressions are unknown. The aim of this study is to further explore the antioxidant status and effect of oxidative stress in GDM tissue. Human placenta, omental and subcutaneous adipose tissue from women with and without GDM were exposed to hypoxanthine (HX)/xanthine oxidase (XO). Cytokine release was analysed by ELISA and cytokine and antioxidant gene expression by RT-PCR. Catalase (CAT) and glutathione reductase (GSR) mRNA expression was higher in GDM (n=18) compared with normal (n=23) placenta. There was no difference in glutathione peroxidase and superoxide dismutase mRNA expression. Antioxidant gene expression was unaltered between normal (n=18) and GDM (n=10) adipose tissue. HX/XO treatment significantly stimulated cytokine release (13/16 cytokines) and cytokine mRNA expression, and decreased antioxidant gene expression (CAT and GSR) in human placenta from normal pregnant women. In GDM placenta, HX/XO only significantly increased the release of 3/16 cytokines, while there was no effect on antioxidant gene expression. In normal and GDM adipose tissues, HX/XO increased proinflammatory cytokine and 8-isoprostane release, while there was no change in antioxidant gene expression. GDM placenta is characterised by increased antioxidant gene expression, and is less responsive to exogenous oxidative stress than tissues obtained from normal pregnant women. This may represent a protective or adaptive mechanism to prevent damage from further oxidative insult in utero as indicated by increased tissue antioxidant expression.
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Department of Obstetrics and Gynaecology, Mercy Perinatal Research Centre, Department of Medicine, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg 3084, Victoria, Australia
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Department of Obstetrics and Gynaecology, Mercy Perinatal Research Centre, Department of Medicine, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg 3084, Victoria, Australia
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Appropriate foetal growth and development is dependent on adequate placental glucose uptake. Oxidative stress regulates glucose uptake in various tissues. The effect of oxidative stress on placental glucose transport is not known. Thus, the aim of this study was to determine the effect of oxidative stress on glucose uptake and glucose transporters (GLUTs) in human placenta. Human placenta was incubated in the absence or presence of 0.5 mM hypoxanthine+15 mU/ml xanthine oxidase (HX/XO) for 24 h. Gene and protein expressions of the GLUTs were analysed by quantitative RT-PCR and western blotting respectively. Glucose uptake was measured using radiolabelled (14C) glucose. HX/XO significantly decreased GLUT1 gene and protein expression and resultant glucose uptake. There was no effect of the antioxidants N-acetylcysteine, catalase and superoxide dismutase or the NF-κB inhibitor BAY 11-0782 on HX/XO-induced decrease in glucose uptake. However, HX/XO treatment significantly decreased both gene and protein expression of SIRT1. In the presence of the SIRT1 activator resveratrol, the decrease in GLUT1 expression and glucose uptake mediated by HX/XO was abolished. Collectively, the data presented here demonstrate that oxidative stress reduces placental glucose uptake and GLUT1 expression by a SIRT1-dependent mechanism.
Translational Proteomics, Baker Medical Research Institute, Baker Heart Research Institute, Melbourne, Victoria 3004, Australia
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Translational Proteomics, Baker Medical Research Institute, Baker Heart Research Institute, Melbourne, Victoria 3004, Australia
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Translational Proteomics, Baker Medical Research Institute, Baker Heart Research Institute, Melbourne, Victoria 3004, Australia
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Processes of human labour include increased oxidative stress, formation of inflammatory mediators (e.g. cytokines) and uterotonic phospholipid metabolites (e.g. prostaglandins). In non-gestational tissues, advanced glycation endproducts (AGE) induce the expression of pro-inflammatory molecules through mitogen-activated protein kinase and nuclear factor κB (NF-κB)-dependent pathways. Thus, the aim of this study was to investigate the effects of AGE on 8-isoprostane (a marker of oxidative stress), pro-inflammatory cytokine and prostaglandin release in human gestational tissues, and to define the signalling pathways involved. Human placenta and gestational membranes (amnion and choriodecidua combined; n=5) were incubated in the absence or presence of AGE–BSA (0.25, 0.5, 1 and 2 mg/ml) for 18 h. AGE significantly increased in vitro release of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, prostaglandin (PG)E2, PGF2α and 8-isoprostane from human placenta and gestational membranes. This was associated with a concomitant increase in NF-κB p65 activation and ERK 1/2 phosphorylation. AGE-stimulated 8-isoprostane, cytokine and prostaglandin production was significantly suppressed by the ERK 1/2 inhibitor U0126 and the NF-κB inhibitor BAY 11-7082. In conclusion, AGE mediates inflammatory actions in human gestational tissues. Protein kinases and the NF-κB pathway play an essential role in AGE signalling in human gestational tissues.
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The aim of this study was to determine the release and regulation of leptin, resistin and adiponectin from human placenta and fetal membranes, and maternal subcutaneous adipose tissue and skeletal muscle obtained from normal and gestational diabetes mellitus (GDM)-complicated pregnancies at the time of Cesarean section. Tissue explants were incubated in the absence (basal control) or presence of 10 μg/ml lipopolysaccharide (LPS), 10, 20 or 40 ng/ml tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8, 1 μM phorbol myristate acetate, 10, 20 and 40 mM glucose, 0.1, 1 and 10 μM insulin and 0.1 1 and 10 μM dexamethasone, progesterone and estrogen. After an 18-h incubation, the medium was collected and the release of leptin, resistin and adiponectin was quantified by ELISA. Human gestational tissues and maternal tissues released immunoreactive leptin, resistin and adiponectin; however, there was no difference in the release of either resistin or adiponectin between normal pregnant women and women with gestational diabetes. The release of leptin was significantly higher in placenta, amnion and choriodecidua obtained from normal pregnant women compared with women with GDM. However, in maternal tissues, the situation was reversed, with adipose tissue and skeletal muscle obtained from women with GDM releasing significantly greater amounts of leptin. In adipose tissue and skeletal muscle the release of leptin was significantly greater in insulin-controlled GDM compared with diet-controlled GDM, and leptin release from adipose tissue was significantly correlated with maternal body mass index. In all tissues tested, there was no effect of incubation with LPS, IL-6, IL-8 or TNF-α on leptin, resistin or adiponectin release. PMA significantly increased the release of resistin from placenta and adipose tissue. Insulin increased placental resistin release, whereas the hormones dexamethasone, progesterone and estrogen significantly decreased placental resistin release. The data presented in this study demonstrate that dysregulation of leptin metabolism and/or function in the placenta may be implicated in the pathogenesis of GDM. Furthermore, resistin release is greatly affected by a variety of inflammatory mediators and hormones.
Mercy Perinatal Research Centre, University of Queensland Centre for Clinical Research, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Mercy Perinatal Research Centre, University of Queensland Centre for Clinical Research, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Mercy Perinatal Research Centre, University of Queensland Centre for Clinical Research, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Gestational diabetes mellitus (GDM) is a significant risk factor for the type 2 diabetes epidemic in many populations. Maternal adipose tissue plays a central role in the pathophysiology of GDM. Thus, the aim of this study was to determine the effect of GDM on the proteome of adipose tissue. Omental adipose tissue was obtained at the time of term Caesarean section from women with normal glucose tolerance (NGT) or GDM. 2D-difference gel electrophoresis (DIGE), followed by mass spectrometry, was used to identify protein spots (n=6 patients per group). Western blotting was used for confirmation of six of the spot differences (n=6 patients per group). We found 14 proteins that were differentially expressed between NGT and GDM adipose tissue (≥1.4-fold, P<0.05). GDM was associated with an up-regulation of four proteins: collagen alpha-2(VI) chain (CO6A2 (COL6A2)), fibrinogen beta chain (FIBB (FGB)), lumican (LUM) and S100A9. On the other hand, a total of ten proteins were found to be down-regulated in adipose tissue from GDM women. These were alpha-1-antitrypsin (AIAT (SERPINA1)), annexin A5 (ANXA5), fatty acid-binding protein, adipocyte (FABP4), glutathione S-transferase P (GSTP (GSTP1)), heat-shock protein beta-1 (HSP27 (HSPB1)), lactate dehydrogenase B chain (LDHB), perilipin-1 (PLIN1), peroxiredoxin-6 (PRX6 (PRDX6)), selenium-binding protein 1 (SBP1) and vinculin (VINC (VCL)). In conclusion, proteomic analysis of omental fat reveals differential expression of several proteins in GDM patients and NGT pregnant women. This study revealed differences in expression of proteins that are involved in inflammation, lipid and glucose metabolism and oxidative stress and added further evidence to support the role of visceral adiposity in the pathogenesis of GDM.
