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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    • "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. "
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    British Journal of Pharmacology 07/2015; 172(18). DOI:10.1111/bph.13241 · 4.84 Impact Factor
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    • "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. "
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    BioMed Research International 09/2014; 2014:145846. DOI:10.1155/2014/145846 · 2.71 Impact Factor
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    • "However, no studies have focused on the effects of hyperglycemia on HBCs. Some studies have demonstrated that diabetes, during pregnancy, alters the expression of placental genes related to markers and mediators of inflammation and leads to impaired fetal growth and programming, which causes several metabolic diseases [16]. The goal of our study was to investigate the direct effects of hyperglycemia on HBCs through in vivo and in vitro systems. "
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