Gestational diabetes reduces adenosine transport in human placental microvascular endothelium, an effect reversed by insulin.
Gestational diabetes mellitus (GDM) courses with increased fetal plasma adenosine concentration and reduced adenosine transport in placental macrovascular endothelium. Since insulin modulates human equilibrative nucleoside transporters (hENTs) expression/activity, we hypothesize that GDM will alter hENT2-mediated transport in human placental microvascular endothelium (hPMEC), and that insulin will restore GDM to a normal phenotype involving insulin receptors A (IR-A) and B (IR-B). GDM effect on hENTs expression and transport activity, and IR-A/IR-B expression and associated cell signalling cascades (p42/44 mitogen-activated protein kinases (p42/44(mapk)) and Akt) role in hPMEC primary cultures was assayed. GDM associates with elevated umbilical whole and vein, but not arteries blood adenosine, and reduced hENTs adenosine transport and expression. IR-A/IR-B mRNA expression and p42/44(mapk)/Akt ratios ('metabolic phenotype') were lower in GDM. Insulin reversed GDM-reduced hENT2 expression/activity, IR-A/IR-B mRNA expression and p42/44(mapk)/Akt ratios to normal pregnancies ('mitogenic phenotype'). It is suggested that insulin effects required IR-A and IR-B expression leading to differential modulation of signalling pathways restoring GDM-metabolic to a normal-mitogenic like phenotype. Insulin could be acting as protecting factor for placental microvascular endothelial dysfunction in GDM.
Cellular and Molecular Physiology Laboratory (CMPL) and Perinatology Research Laboratory (PRL), Medical Research Centre (CIM), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Carlos
C
Salomón
Francisco
F
Westermeier
Carlos
C
Puebla
Pablo
P
Arroyo
Enrique
E
Guzmán-Gutiérrez
Fabián
F
Pardo
Andrea
A
Leiva
Paola
P
Casanello
Luis
L
Sobrevia
D000241:Adenosine / Q000097:blood / Q000378:metabolism*; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D016640:Diabetes, Gestational / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010920:Placenta / Q000098:blood supply*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D007328:Insulin; D020033:Protein Isoforms; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; D011972:Receptor, Insulin; D000241:Adenosine