Abstract
Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous) uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.
Highlights
Glucose, a primary substrate for fetal growth, is transported across the human placenta via the GLUT1 glucose transporter that is found in both the microvillous and basal membranes of the syncytiotrophoblast barrier layer
Basal membrane GLUT1 was reduced by 43% in the control perfusion compared to the immediate controls, but in the Insulin-Like Growth Factor I (IGF-I) perfusions basal membrane GLUT1 expression was increased by 38% compared to the immediate controls (p, 0.05, one sample t test, n = 4). These studies examined the role of IGF-I in the regulation of GLUT1 protein expression in trophoblast cells
We hypothesized that IGF-I would up-regulate GLUT1 expression on the basal surface, the rate limiting step in maternal to fetal glucose transport
Summary
A primary substrate for fetal growth, is transported across the human placenta via the GLUT1 glucose transporter that is found in both the microvillous and basal membranes of the syncytiotrophoblast barrier layer. GLUT1 glucose transporters are asymmetrically distributed, being several fold higher on the microvillous (maternal facing) than basal (fetal-facing) membrane [1,2]. The importance of GLUT 1 in fetal growth is clear. GLUT1 transporter expression is increased in the basal membrane in diabetic pregnancies [4,5], while a decrease in basal membrane GLUT1 expression has been shown in altitude-induced hypoxia, concomitant with reduced fetal growth [6]. In addition to the asymmetric distribution of the GLUT1 glucose transporters, varied rates of glucose consumption in syncytiotrophoblast cells have been shown to be an important factor regulating directional flux of glucose from the maternal to the fetal circulation [7]
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