Glucose and metformin modulate human first trimester trophoblast function: a model and potential therapy for diabetes-associated uteroplacental insufficiency.
OBJECTIVE
Diabetes confers an increased risk of preeclampsia, but its pathogenic role in preeclampsia is poorly understood. The objective of this study was to elucidate the effects of excess glucose on trophoblast function and whether any changes could be reversed by metformin.


METHODS
The human first trimester trophoblast cell line (Sw.71) was treated with glucose at 5, 10, 25, and 50 mm, in the presence and absence of metformin. Trophoblast migration was quantified and supernatant cytokine, chemokine, and angiogenic factors measured.


RESULTS
Increasing concentrations of glucose significantly increased trophoblast secretion of the inflammatory cytokines/chemokines: IL-1β, IL-6, IL-8, GRO-α, RANTES, and G-CSF; significantly increased trophoblast secretion of the anti-angiogenic factors sFlt-1 and sEndoglin; and significantly decreased trophoblast migration. Excess glucose-induced trophoblast IL-1β production was inhibited by disabling the Nalp3/ASC inflammasome. Metformin partially reduced the glucose-induced inflammatory response, but had no effect on the anti-angiogenic or antimigratory response.


CONCLUSIONS
Excess glucose induced a pro-inflammatory, anti-angiogenic, and antimigratory state in first trimester trophoblast cells. Glucose-induced trophoblast IL-1β secretion was mediated by the inflammasome. Glucose-induced inflammation was partially reversed by metformin. These findings demonstrate the pleiotropic effects of hyperglycaemia on the trophoblast, providing potential explanations for the strong link between diabetes and preeclampsia.
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Christina S
CS
Han
Melissa A
MA
Herrin
Mary C
MC
Pitruzzello
Melissa J
MJ
Mulla
Erika F
EF
Werner
Christian M
CM
Pettker
Clare A
CA
Flannery
Vikki M
VM
Abrahams
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D000071063:Endoglin; D005260:Female; D005947:Glucose / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD; C483024:CCL5 protein, human; C475829:CXCL1 protein, human; D002352:Carrier Proteins; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; C064206:ENG protein, human; D000071063:Endoglin; D007378:Interleukins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011956:Receptors, Cell Surface; D016179:Granulocyte Colony-Stimulating Factor; D008687:Metformin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D005947:Glucose
Diabetes; glucose; metformin; preeclampsia; trophoblast