Endocrine Abstracts

The mammalian target of rapamycin (mTOR) is a serine kinase that couples energy and nutrient abundance to cell growth and is critically involved in the onset and progression of diabetes, cancer and ageing. Placental mTOR is involved in nutrient sensing and transfer to the fetus. Animal models suggest that placental mTOR is upregulated in pregnancies complicated by gestational diabetes (GDM). Our aim was to characterize expression, and cellular localization of mTOR and whether the activated fraction is affected by GDM. Our study consisted of i) GDM-mothers (n=40) and their offspring and ii) mothers (n=33) with normal pregnancies (non-GDM) and their infants. At delivery, fetal glucose was measured in cord blood and total and phospho-mTOR (Ser2448) expression were determined in placental biopsies using Western blot (WB) and immunohistochemistry (IHC) analysis. Newborn anthropometric parameters were also determined at delivery. GDM pregnant women were older (30.81±4.87; 33.39±5.38, P<0.02) and presented with higher fasting glucose levels than non-GDM (94.82±19.96 mg/dl; 73.08±9.77 mg/dl; P<0.001). No significant difference was found in birth weight or baby length between GDM and non-GDM infants. IHC analysis showed that both total and activated mTOR were predominantly expressed in trophoblasts and to a lesser extend in synciotrophoblasts, in both GDM and non-GDM placentas. GDM placentas exhibited a higher mTOR H-score compared to non-GDM (P<0.009), and WB analysis showed a higher phospho-mTOR signal intensity (P=0.047) in the same group. However, total mTOR expression was relatively increased in GDM placentas resulting in a decreased phospho/total (P/T) ratio in GDM than non-GDM placental tissues (0.95 vs 0.8, P=0.001). mTOR expression was increased in both GDM syncitiotrophoblasts and endothelial cells compared to non GDM (P<0.001) whereas a reduced signal was detected in stromal phospho-mTOR (P=0.004). No difference was found in trophoblasts or endothelial cells between the two study groups suggesting that activation of this kinase is tightly regulated and is relatively independent of changes in total kinase levels. The upregulation of the total mTOR levels led to a decreased P/T mTOR ratio in GDM syncytiotrophoblasts compared to non-GDM (P<0.001). A positive correlation was found between endothelial P/T mTOR ratio and baby length (P=0.025) and a negative correlation with BMI, maternal fasting glucose and fetal glucose (P=0.005; P=0.025; P=0.026 respectively). Placental mTOR/PmTOR expression is differentially regulated across different placental cell types and is sensitive to hyperglycaemia associated with gestational diabetes mellitus.