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


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.


Available from: Patrick M Catalano, Aug 30, 2015
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    • "The number of CD68+ or CD14+ cells has been found increased in the placentas of GDM women, indicating fetal macrophage activation which may contribute to systemic inflammation and insulin resistance in GDM [95]. In addition, mRNA expression levels of IL-6 and TNF were higher in the placentas of GDM women, which could promote intraplacental inflammatory cascades through specific gene tran- scription [97, 98]. "
    [Show abstract] [Hide abstract] ABSTRACT: With increasing rates of obesity and new diagnostic criteria for gestational diabetes mellitus (GDM), the overall prevalence of GDM is increasing worldwide. Women with GDM have an increased risk of maternal and fetal complications during pregnancy as well as long-term risks including higher prevalence of type 2 diabetes mellitus and cardiovascular disease. In recent years, the role of immune activation and inflammation in the pathogenesis of GDM has gained increasing attention. This monograph explores the current state of the literature as regards the expression of markers of inflammation in the maternal circulation, placenta, and adipose tissue of women with GDM.
    Full-text · Article · Apr 2016 · Current Diabetes Reports
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    • "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
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    • "Although animals studies provide support for epigenetic modifications due to maternal obesity or a high fat diet, only few human studies have explored these associations [126]. Small studies among pregnant women suggested epigenetic changes of placental genes induced by maternal obesity and impaired maternal glucose tolerance [121,128129130. Also, a human study among 88 mother–child pairs suggested that maternal weight gain in early pregnancy , but not maternal prepregnancy body mass index or weight gain in later pregnancy, might be associated with epigenetic modifications in offspring cord blood [131]. Epigenetic modifications as well as other mechanisms may be involved in adiposity, cardiovascular and metabolic developmental adaptations. "
    [Show abstract] [Hide abstract] ABSTRACT: Maternal obesity during pregnancy is an important public health problem in Western countries. Currently, obesity prevalence rates in pregnant women are estimated to be as high as 30 %. In addition, approximately 40 % of women gain an excessive amount of weight during pregnancy in Western countries. An accumulating body of evidence suggests a long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and metabolic related health outcomes in the offspring in fetal life, childhood and adulthood. In this review, we discuss results from recent studies, potential underlying mechanisms and challenges for future epidemiological studies.
    Preview · Article · Sep 2015 · European Journal of Epidemiology
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