Article

Gestational Diabetes Induces Placental Genes for Chronic Stress and Inflammatory Pathways

Department of Reproductive Biology, Schwartz Center for Metabolism and Nutrition, University School of Medicine at MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Diabetes (Impact Factor: 8.1). 01/2004; 52(12):2951-8. DOI: 10.2337/diabetes.52.12.2951
Source: PubMed

ABSTRACT

A physiological state of insulin resistance is required to preferentially direct maternal nutrients toward the feto-placental unit, allowing adequate growth of the fetus. When women develop gestational diabetes mellitus (GDM), insulin resistance is more severe and disrupts the intrauterine milieu, resulting in accelerated fetal development with increased risk of macrosomia. As a natural interface between mother and fetus, the placenta is the obligatory target of such environmental changes. However, the molecular basis for the imbalance that leads to fetal, neonatal, and adult metabolic compromises is not well understood. We report that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation. Within the 435 transcripts reproducibly modified, genes for stress-activated and inflammatory responses represented the largest functional cluster (18.5% of regulated genes). Upregulation of interleukins, leptin, and tumor necrosis factor-alpha receptors and their downstream molecular adaptors indicated an activation of pathways recruiting stress-activated protein/c-Jun NH(2)-terminal kinases. Transcriptional activation of extracellular matrix components and angiogenic activators pointed to a major structural reorganization of the placenta. Thus, placental transcriptome emerges as a primary target of the altered environment of diabetic pregnancy. The genes identified provide the basis to elucidate links between inflammatory pathways and GDM-associated insulin resistance.

Download full-text

Full-text

Available from: Patrick M Catalano, Aug 30, 2015
  • Source
    • "If the duration or extent of the diabetic insult, including maternal hyperglycemia, hyperinsulinemia , or dyslipidemia, exceeds the placental capacity to mount adequate responses, then excessive fetal growth may ensue [64]. Furthermore gene expression studies suggest that GDM is characterized by changes in trophoblast cells that include upregulation of genes involved in a multitude of cellular functions including, immune response, organ development, regulation of cell death and also genes regulating inflammatory responses and endothelial reorganization reflecting a state of chronic systemic inflammation of placentas of women with GDM that could ultimately lead to the chronic fetal hypoxia [65,66]. Fetal glucose production is minimal, therefore, the fetus depends almost completely on the maternal glucose supply. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gestational diabetes mellitus is defined by new-onset glucose intolerance during pregnancy. About 2-5% of all pregnant women develop gestational diabetes during their pregnancies and the prevalence has increased considerably during the last decade. This metabolic condition is manifested when pancreatic β-cells lose their ability to compensate for increased insulin resistance during pregnancy, however, the pathogenesis of the disease remains largely unknown. Gestational diabetes is strongly associated with adverse pregnancy outcome as well as with long-term adverse effects on the offspring which likely occurs due to epigenetic modifications of the fetal genome. In the current review we address gestational diabetes and the short and long term complications for both mothers and offspring focusing on the importance of fetal programming in conferring risk of developing diseases in adulthood.
    Full-text · Article · Dec 2015 · Placenta
  • Source
    • "In GDM, placental transcriptome analysis has shown the activation of multiple signal transduction pathways, involving inflammatory mediators, such as TNF-α, IL-1 and leptin, which may contribute to cell hypertrophy and a dysfunctional vasculosyncytial membrane (Radaelli et al., 2003). These results suggest that the fetus of diabetic mothers develops in an inflammatory milieu. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperglycemic memory describes the progression of diabetic complications during subsequent periods of improved glycemia.We addressed the hypothesis that transient hyperglycemia causes aberrant cyclooxygenase(COX)-2 expression in human umbilical vein endothelial cells(HUVEC) in response to interleukin(IL)-1β through the induction of long-lasting epigenetic changes involving microRNA-16(miR-16), a post-transcriptional modulator of COX-2 expression. Studies were performed in HUVEC collected from gestational diabetes mellitus(GDM)(dHUVEC) and normal women(nHUVEC). In dHUVEC treated with IL-1β, we found enhanced expression of COX-2 mRNA and protein and increased generation of prostanoids[the most abundant was the promitogenic prostaglandin(PG)F2α ]. COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 downregulation and c-Myc induction(a repressor of miR expression). dHUVEC showed higher cellular proliferation in response to IL-1β which was abrogated by COX-2 inhibition and PGF2α receptor antagonism. Comparable changes of COX-2 mRNA, miR-16 and c-Myc detected in dHUVEC were produced in nHUVEC exposed to transient high glucose and then stimulated with IL-1β under physiological glucose levels. Under these experimental conditions, enhanced superoxide anion production was detected. Our results describe a possible mechanism operating in GDM that links enhanced superoxide anion production and epigenetic changes, associated with hyperglycemic memory, to endothelial dysfunction through dysregulated post-transcriptional control of COX-2 gene expression in response to inflammatory stimuli. The association of conventional therapy for glycemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of GDM complications. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · British Journal of Pharmacology
  • Source
    • "Expression of both IL6 and TNFA is sensitive to oxidative stress. Indeed, hyperglycemia stimulates expression of IL6 in trophoblasts [118] and placental expression of IL6 and TNFA is increased [113, 119, 120], but their levels in the fetal circulation are unchanged or even reduced [121, 122]. Thus, TNFA and IL6 may affect placental angiogenesis locally, that is, in a paracrine manner. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors.
    Full-text · Article · Sep 2014 · BioMed Research International
Show more