Gestational diabetes mellitus (GDM) is associated with increased placental thickness, inflammation and fibrosis. The renin-angiotensin system (RAS) is a key regulator of placental development, acting through receptors including insulin-regulated aminopeptidase (IRAP/AT4R). Notably, IRAP is associated with glucose metabolism as it can promote leptin production and is co-regulated with glucose transporter type-4 (GLUT4). Tissue RAS activity is upregulated in non-pregnant diabetics, but nothing is known about placental RAS activity in GDM. We examined the impact of hyperglycaemia on placental trophoblast expression of IRAP, GLUT4 and leptin, and characterised their placental and circulating levels in GDM pregnancies.
Primary trophoblast cells were isolated from placentae of term, uncomplicated pregnancies (n=5) and cultured in normoglycaemic [5mM glucose] or hyperglycaemic [25mM glucose] conditions. Placental tissue and matched maternal blood were collected from term, uncomplicated (n=44) and GDM pregnancies (n=39). Expression of IRAP, GLUT4 and leptin mRNA was measured by qPCR. IRAP and leptin protein levels were quantified using immunoblot and ELISA.
Hyperglycaemia increased trophoblast IRAP and GLUT4 mRNA (p=0.021 and p<0.009, respectively) and decreased leptin mRNA (p<0.001). Placental expression of IRAP, GLUT4 and leptin mRNA was similar in uncomplicated and GDM pregnancies, as were levels of IRAP and leptin. Management of GDM by diet or insulin had no effect on mRNA or protein expression. Circulating IRAP was similar between groups, however GDM was associated with increased circulating leptin (p=0.014), which was positively correlated with pre-pregnancy BMI (rho=0.727, p<0.001).
This study is the first to characterise placental IRAP, GLUT4 and leptin in GDM and establish that their expression in trophoblasts is sensitive to hyperglycaemia. Our data suggest that trophoblast signalling via IRAP may be upregulated in GDM, promoting glucose uptake via GLUT4 and potentiating placental growth. Further cell-specific research in GDM placentae is warranted to elucidate the role of IRAP in mediating placental abnormalities in GDM.