Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus
Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. It affects more than 17 million women each year and causes adverse consequences for both mother and baby. Previous research has observed that the placenta plays an important role in the pathogenesis of GDM, s...
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| Format: | Thesis |
| Language: | English |
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2020
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| _version_ | 1826312483867983872 |
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| author | Kandzija, N |
| author2 | Vatish, M |
| author_facet | Vatish, M Kandzija, N |
| author_sort | Kandzija, N |
| collection | OXFORD |
| description | Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. It affects more than 17 million women each year and causes adverse consequences for both mother and baby. Previous research has observed that the placenta plays an important role in the pathogenesis of GDM, since delivery of the placenta results in the immediate reversal of diabetic symptoms. The aim of this thesis is to investigate the nature of the placenta’s role in GDM, building on the knowledge that the organ releases extracellular vesicles (EVs) into the maternal circulation from six weeks gestation until delivery. EVs carry a variety of ligands, including both proteins and RNA species, between the cells. As such, they have an important role in cell-cell communication in both physiological and pathophysiological conditions, and may provide novel biomarkers of disease. We hypothesized that placental EVs might carry factors impacting insulin availability, a hallmark of pregnancy altered during the establishment of GDM. We identified two novel biomarkers (dipeptidyl peptidase 4 (DPPIV) and insulin receptor (IR)) on placental EVs. DPPIV is a glycoprotein that rapidly degrades incretin hormones, which are known to increase insulin secretion, and thus regulate glucose homeostasis. DPPIV inhibitors are established as therapeutic agents for type 2 diabetes mellitus, and we confirmed that they can be used to inhibit placental DPPIV-EV activity. IR is a key regulator of glucose uptake by skeletal muscles and adipose cells. We showed that placental IR-EVs can act as decoy receptors capable of neutralising maternal insulin. We demonstrated that GDM patients exhibited significantly higher levels of circulating placental DPPIV-EVs and IR-EVs. The final aim of this project was to characterise the protein cargo of placental EVs from GDM pregnancy using mass spectrometry. We identified 56 proteins as differentially expressed between GDM and normal pregnancy. In conclusion, this DPhil project shows that STB-EVs carry biologically active molecules that have the potential to regulate maternal insulin levels in GDM and could represent biologically plausible biomarkers for the disease. |
| first_indexed | 2024-03-07T08:29:40Z |
| format | Thesis |
| id | oxford-uuid:c108c3f9-e8ac-4eef-b667-b395f6dff7b5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:29:40Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:c108c3f9-e8ac-4eef-b667-b395f6dff7b52024-03-04T10:07:26ZSyncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitusThesishttp://purl.org/coar/resource_type/c_db06uuid:c108c3f9-e8ac-4eef-b667-b395f6dff7b5Reproductive healthEnglishHyrax Deposit2020Kandzija, NVatish, MBecker, CMitchell, DZhang, WCoward, KGestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. It affects more than 17 million women each year and causes adverse consequences for both mother and baby. Previous research has observed that the placenta plays an important role in the pathogenesis of GDM, since delivery of the placenta results in the immediate reversal of diabetic symptoms. The aim of this thesis is to investigate the nature of the placenta’s role in GDM, building on the knowledge that the organ releases extracellular vesicles (EVs) into the maternal circulation from six weeks gestation until delivery. EVs carry a variety of ligands, including both proteins and RNA species, between the cells. As such, they have an important role in cell-cell communication in both physiological and pathophysiological conditions, and may provide novel biomarkers of disease. We hypothesized that placental EVs might carry factors impacting insulin availability, a hallmark of pregnancy altered during the establishment of GDM. We identified two novel biomarkers (dipeptidyl peptidase 4 (DPPIV) and insulin receptor (IR)) on placental EVs. DPPIV is a glycoprotein that rapidly degrades incretin hormones, which are known to increase insulin secretion, and thus regulate glucose homeostasis. DPPIV inhibitors are established as therapeutic agents for type 2 diabetes mellitus, and we confirmed that they can be used to inhibit placental DPPIV-EV activity. IR is a key regulator of glucose uptake by skeletal muscles and adipose cells. We showed that placental IR-EVs can act as decoy receptors capable of neutralising maternal insulin. We demonstrated that GDM patients exhibited significantly higher levels of circulating placental DPPIV-EVs and IR-EVs. The final aim of this project was to characterise the protein cargo of placental EVs from GDM pregnancy using mass spectrometry. We identified 56 proteins as differentially expressed between GDM and normal pregnancy. In conclusion, this DPhil project shows that STB-EVs carry biologically active molecules that have the potential to regulate maternal insulin levels in GDM and could represent biologically plausible biomarkers for the disease. |
| spellingShingle | Reproductive health Kandzija, N Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title | Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title_full | Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title_fullStr | Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title_full_unstemmed | Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title_short | Syncytiotrophoblast extracellular vesicles:their role in gestational diabetes mellitus |
| title_sort | syncytiotrophoblast extracellular vesicles their role in gestational diabetes mellitus |
| topic | Reproductive health |
| work_keys_str_mv | AT kandzijan syncytiotrophoblastextracellularvesiclestheirroleingestationaldiabetesmellitus |