Background
The hexosamine signaling pathway (HSP) leads to the posttranslational addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins, altering their fate and function. Fructose–6-phosphate is funneled from the glycolytic pathway into the HSP by glutamine:fructose-6-phosphate aminotransferase (GFAT1). O-GlcNAc transferase (OGT1) adds O-GlcNAc and the O-GlcNAcase OGA removes it. GFAT1 acts as a nutrient sensor and its activity is dependent on glucose and amino acid metabolism. In type 2 diabetes mellitus, GFAT1 mRNA levels and activity are increased in skeletal muscle. O-GlcNAc levels are associated with the development of insulin resistance. This study aims to analyze placental expression of important enzymes in the HSP in GDM.
Methods
mRNA was extracted from placentas from 10 women with and 30 women without GDM matched for BMI, gestational age at delivery and birthweight. Expression of GFAT1, OGT1 and OGA was assessed by QPCR using the geometric mean of expression of TBP and B-Actin as endogenous controls. Non-parametric methods were used to compare expression between the groups. Immunohistochemical staining for GFAT1 was performed on five GDM and five control placental samples.
Results
Placental mRNA expression of GFAT1 was higher in women with GDM (2.16 (1.21-6.78) median (IQR) AU) than in women without (0.76 (0.48-2.25), P<0.05). OGT1 expression also was higher in women with GDM (2.53 (0.89-8.18) vs. 0.49 (0.16-2.87), P<0.05). There was no difference in the expression of OGA. The expression of these genes was not correlated with maternal BMI or infant birth weight. Immunohistochemical staining demonstrated preferential staining of the placental synyctiotrophoblast and endothelial cells.
Conclusion
Maternal GDM is associated with an increase in the placental expression of two key enzymes in the HSP. The direction of change is suggestive of a funneling of proteins toward the HSP and increased O-GlcNAc cycling. These changes are not associated with changes in infant birth weight.