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Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta.

ABSTRACT: CONTEXT:Placental transport capacity influences fetal glucose supply. The syncytiotrophoblast is the transporting epithelium in the human placenta, expressing glucose transporters (GLUT) and insulin receptors (IR) in its maternal-facing microvillous (MVM) and fetal-facing basal plasma membrane (BM). OBJECTIVE:The objectives of this study were to (1) determine the expression of the insulin-sensitive GLUT4 glucose transporter and IR in the syncytiotrophoblast plasma membranes across gestation in normal pregnancy and in pregnancies complicated by maternal obesity and (2) assess the effect of insulin on GLUT4 plasma membrane trafficking in human placental explants. DESIGN, SETTING, PARTICIPANTS:Placental tissue was collected across gestation from women with normal body mass index (BMI) and obese mothers with appropriate for gestational age (AGA) and macrosomic infants. MVM and BM were isolated. MAIN OUTCOME MEASURES:Protein expression of GLUT4, GLUT1 and IR were determined by western blot. RESULTS:GLUT4 was exclusively expressed in the BM and IR was predominantly expressed in the MVM, with increasing expression across gestation. BM GLUT1 expression was increased and BM GLUT4 expression was decreased in obese women delivering macrosomic babies. In placental villous explants incubation with insulin stimulated Akt (S473) phosphorylation (+76%, p=0.0003, n=13) independent of maternal BMI and increased BM GLUT4 protein expression (+77%, p=0.0013, n=7) in placentas from lean but not obese women. CONCLUSION:We propose that maternal insulin stimulates placental glucose transport by promoting GLUT4 trafficking to the BM, which may enhance glucose transfer to the fetus in response to postprandial hyperinsulinemia in women with normal BMI.

SUBMITTER: James-Allan LB

PROVIDER: S-EPMC6688457 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Project description:The fruit fly Drosophila melanogaster is an excellent model system for studies of genes controlling development and disease. However, its applicability to physiological systems is less clear because of metabolic differences between insects and mammals. Insulin signaling has been studied in mammals because of relevance to diabetes and other diseases but there are many parallels between mammalian and insect pathways. For example, deletion of Drosophila Insulin-Like Peptides resulted in 'diabetic' flies with elevated circulating sugar levels. Whether this situation reflects failure of sugar uptake into peripheral tissues as seen in mammals is unclear and depends upon whether flies harbor the machinery to mount mammalian-like insulin-dependent sugar uptake responses. Here we asked whether Drosophila fat cells are competent to respond to insulin with mammalian-like regulated trafficking of sugar transporters. Transgenic Drosophila expressing human glucose transporter-4 (GLUT4), the sugar transporter expressed primarily in insulin-responsive tissues, were generated. After expression in fat bodies, GLUT4 intracellular trafficking and localization were monitored by confocal and total internal reflection fluorescence microscopy (TIRFM). We found that fat body cells responded to insulin with increased GLUT4 trafficking and translocation to the plasma membrane. While the amplitude of these responses was relatively weak in animals reared on a standard diet, it was greatly enhanced in animals reared on sugar-restricted diets, suggesting that flies fed standard diets are insulin resistant. Our findings demonstrate that flies are competent to mobilize translocation of sugar transporters to the cell surface in response to insulin. They suggest that Drosophila fat cells are primed for a response to insulin and that these pathways are down-regulated when animals are exposed to constant, high levels of sugar. Finally, these studies are the first to use TIRFM to monitor insulin-signaling pathways in Drosophila, demonstrating the utility of TIRFM of tagged sugar transporters to monitor signaling pathways in insects.

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Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta.

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