Gestational diabetes induces placental genes for chronic stress and inflammatory pathways
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.
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ABSTRACT: Maternal diabetes causes placental and foetal abnormalities in both rat and humans; however, its effect is less well documented in the mouse. We used a standard approach to induce manifest diabetes in pregnant mice and assessed morphology, function and gene expression in the placentas isolated from these females. We found that diabetic placentas exhibit a consistent abnormal phenotype characterized by increased junctional zone cross sectional area. Lipid profiling of diabetic foetuses and placentas showed that the placental phenotypes do not compromise the lipid transport function of this organ. In a genome-wide survey of mRNA expression by using cDNA micro-arrays, we identified 118 ESTs, corresponding to 59 annotated genes, with differential expression in the diabetic placentas. A significant proportion of these known is involved in metabolism, immunity and defence, and signal transduction. In addition, we found two imprinted genes, Igf2 and Gatm, which exhibited altered expression. The expression of other imprinted genes, Peg1, Gtl2, Peg3, Igf2r and Grb10, was determined by quantitative RT-PCR. For all of these genes, slight changes in gene expression were observed between diabetic placentas and control placentas. Our study thus provides the basis for future work that will address gene action in the diabetic mouse placenta.Archives of Physiology and Biochemistry 05/2008; 114(2):99-110. DOI:10.1080/13813450802033776
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ABSTRACT: Preeclampsia and diabetes are complications of pregnancy that contribute to maternal and perinatal mortality worldwide. Results emerging from molecular studies of placentae may elucidate etiologically important genomic alterations. Appropriate application of real time reverse transcription (RT) PCR in comparative gene expression studies requires endogenous housekeeping genes to normalize between sample variations. Ideal housekeeping genes must have stable tissue expression, but few have been specifically studied in the placenta. We sought to identify candidate control genes by analyzing seven functionally distinct housekeeping genes (B2M, GAPDH, HMBS, HPRT, SDHA, TBP, YWHAZ) for their expression stability and level in the placenta. mRNA isolated from 20 placentae was analyzed for gene expression using RT-PCR. Expression stability (M) was assessed using normalization strategies previously used for other tissues. TBP and SDHA were the most stable, with an average expression stability of M = 0.43, followed by YWHAZ (M = 0.44) > HPRT (M = 0.53) > HMBS (M = 0.57) > GAPDH (M = 0.61) > B2M (M = 0.69). The genes tested ranged in abundance, with an approximately 300-fold increase from the lowest (HMBS) to the highest (B2M). By using TBP, SDHA and YWHAZ, with greater expression stability than those housekeeping genes commonly used in placenta studies, gene expression profile comparisons will have more sensitivity and specificity.Placenta 09/2005; 26(8-9):601-7. DOI:10.1016/j.placenta.2004.09.009 · 3.29 Impact Factor
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ABSTRACT: A low-grade systemic inflammation is concomitant in diabetes. There is a pathophysiological relation between gestational diabetes mellitus and type 2 diabetes mellitus, which was further supported by significantly elevated risk of type 2 diabetes in women with a history of previous gestational diabetes mellitus. We investigated the relation between low-grade systemic inflammation expressed as C-reactive protein and gestational diabetes in non-obese pregnant women. This study included 20 non-obese pregnant women with gestational diabetes mellitus and 30 non-obese pregnant women without gestational diabetes mellitus as a control group. The body mass index of all the subjects were < 25 kg/m2. During 26-28 gestational weeks 100-g oral glucose tolerance test was performed and simultaneously fasting C-reactive protein levels were measured. Serum median C-reactive protein level was higher in patients with gestational diabetes mellitus (p = 0.0001). C-reactive protein was strongly associated with glycemic parameters and weight gain during pregnancy. A model consisting of glucose intolerance, age, parity, and weight gain during pregnancy accounted for 61% of the variance in log C-reactive protein. We demonstrated that serum C-reactive protein level was related with gestational diabetes mellitus and weight gain during pregnancy in late second and early third trimesters.The Tohoku Journal of Experimental Medicine 08/2005; 206(4):341-5. DOI:10.1620/tjem.206.341 · 1.28 Impact Factor