Placental Glucose Transporter Expression Is Regulated

Although glucocorticoids play important roles in development and fetal programming, they are widely used for treatment of a variety of diseases during pregnancy. In various tissues, glucocorticoids downregulate glucose transport systems; however, their effects on glucose transporters in the placenta are unknown. In the present study, the glucose carrier proteins GLUT1 and GLUT3 were localized in the trophoblast and endothelium of the human, rat, and mouse placenta. Subsequently, it was investigated whether glucocorticoids affect messenger ribonucleic acid and protein expression of these molecules by Northern and Western blotting using 1) human term placental trophoblast cells cultured in the presence or absence of 0.5, 5, and 50 mmol/L triamcinolone; 2) placentas of rats that received a single ip dose of 0.38 mg/kg triamcinolone; and 3) placentas of transgenic mice bearing an antisense glucocorticoid receptor gene construct. In all of these systems, both glucose transporters were significantly downregulated (P , 0.05), with the exception of increased GLUT3 messenger ribonucleic acid and protein levels in transgenic mice. The results demonstrate that triamcinolone is a potent regulator of placental GLUT1 and GLUT3 expression involving the glucocorticoid receptor. We speculate that impaired expression of placental glucose transporters after glucocorticoid administration might contribute to the adverse side-effects, the foremost of which is a growth-retarded fetus, of this treatment during pregnancy. (J Clin Endocrinol Metab 84: 1445–1452, 1999) E placental (maternal to fetal) transfer of glucose, the primary substrate for fetal oxidative metabolism, is crucial to sustain the normal development and survival of the fetus in utero because its own glucose production is minimal (1). Glucose transport across the placenta is mediated by stereospecific, sodium-independent, facilitated diffusion along a (mostly maternal to fetal) concentration gradient (2). The process is mediated by specific isoforms of a family of transporter proteins, rendering substrate entry about 10,000 times faster than that calculated for diffusion across the lipid membrane layer (3). These transporters are about 500 amino acids in length and belong to a family of integral membrane glycoproteins with 12 membrane-spanning domains. Despite the high sequence similarity, the glucose transporters are encoded by seven different genes, designated GLUT1-GLUT7 (4), which are translated into protein, with the exception of the pseudogene GLUT6 (5). Whereas GLUT2–5 and GLUT7 are expressed in a highly tissue-specific manner, GLUT1 protein is nearly ubiquitous. Humoral or endocrine factors regulating transplacental glucose transfer, in addition to the maternal to fetal concentration gradient, are largely unknown. Despite the presence of insulin receptors, placental glucose transport and metabolism are insulin independent (6, 7). Glucose itself can upor down-regulate placental GLUT1 (8, 9). Glucocorticoids (GC) specifically inhibit glucose transport in a variety of peripheral tissues, such as skeletal muscle, adipocytes, and endothelial cells (10–15). High affinity, low capacity GC receptors (GR) have been identified in the placenta of various species, including man, rat, and mouse (16–20). Thus, it is reasonable to hypothesize that GCs can regulate glucose transporter expression in the placenta similar to that in the aforementioned tissues. This would have important clinical implications, because GC-induced down-regulation of the placental glucose transport system(s) may contribute to the genesis of the deleterious side-effects of GC treatment during pregnancy, such as the higher incidence of growth-retarded fe-