Gestational Diabetes Induces Placental Genes for Chronic Stress and Inflammatory Pathways

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 NH2-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. Keywords: other To characterize gene targets that determine altered placental functions, the global pattern of gene expression was analyzed in placenta from matched control subjects and GDM pregnancies. Of 22,823 gene sequences surveyed, 8,627 ± 172 were present in control subjects and 9,378 ± 165 in GDM, representing placental transcriptome. The consecutive screening filters that we applied allowed us to narrow these numbers to 2,682 genes eligible for analysis. The average fold change value was then calculated for all pairwise comparisons, resulting in the final selection of 435 genes significantly modified in GDM.