Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus
Abstract Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here,...
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2021-08-01
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Series: | Journal of Translational Medicine |
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Online Access: | https://doi.org/10.1186/s12967-021-02999-9 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Soumyalekshmi Nair Dominic Guanzon Nanthini Jayabalan Andrew Lai Katherin Scholz-Romero Priyakshi Kalita de Croft Valeska Ormazabal Carlos Palma Emilio Diaz Elizabeth A. McCarthy Alexis Shub Jezid Miranda Eduard Gratacós Fátima Crispi Gregory Duncombe Martha Lappas H. David McIntyre Gregory Rice Carlos Salomon |
spellingShingle |
Soumyalekshmi Nair Dominic Guanzon Nanthini Jayabalan Andrew Lai Katherin Scholz-Romero Priyakshi Kalita de Croft Valeska Ormazabal Carlos Palma Emilio Diaz Elizabeth A. McCarthy Alexis Shub Jezid Miranda Eduard Gratacós Fátima Crispi Gregory Duncombe Martha Lappas H. David McIntyre Gregory Rice Carlos Salomon Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus Journal of Translational Medicine Pregnancy Exosomes miRNAs Insulin resistance Skeletal muscle |
author_facet |
Soumyalekshmi Nair Dominic Guanzon Nanthini Jayabalan Andrew Lai Katherin Scholz-Romero Priyakshi Kalita de Croft Valeska Ormazabal Carlos Palma Emilio Diaz Elizabeth A. McCarthy Alexis Shub Jezid Miranda Eduard Gratacós Fátima Crispi Gregory Duncombe Martha Lappas H. David McIntyre Gregory Rice Carlos Salomon |
author_sort |
Soumyalekshmi Nair |
title |
Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus |
title_short |
Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus |
title_full |
Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus |
title_fullStr |
Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus |
title_full_unstemmed |
Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus |
title_sort |
extracellular vesicle-associated mirnas are an adaptive response to gestational diabetes mellitus |
publisher |
BMC |
series |
Journal of Translational Medicine |
issn |
1479-5876 |
publishDate |
2021-08-01 |
description |
Abstract Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. Methods Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. Results A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. Conclusions During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM. |
topic |
Pregnancy Exosomes miRNAs Insulin resistance Skeletal muscle |
url |
https://doi.org/10.1186/s12967-021-02999-9 |
work_keys_str_mv |
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doaj-459eca6bdc89459c879879f07f4b0b452021-08-22T11:09:31ZengBMCJournal of Translational Medicine1479-58762021-08-0119111710.1186/s12967-021-02999-9Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitusSoumyalekshmi Nair0Dominic Guanzon1Nanthini Jayabalan2Andrew Lai3Katherin Scholz-Romero4Priyakshi Kalita de Croft5Valeska Ormazabal6Carlos Palma7Emilio Diaz8Elizabeth A. McCarthy9Alexis Shub10Jezid Miranda11Eduard Gratacós12Fátima Crispi13Gregory Duncombe14Martha Lappas15H. David McIntyre16Gregory Rice17Carlos Salomon18Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandFaculty of Biological Sciences, Pharmacology Department, University of ConcepcionExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandFaculty of Medicine, Department of Obstetrics and Gynaecology, University of ConcepcionDepartment of Obstetrics and Gynaecology, University of MelbourneDepartment of Obstetrics and Gynaecology, University of MelbourneFetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER)Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER)Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER)Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandDepartment of Obstetrics and Gynaecology, University of MelbourneMater Research, Faculty of Medicine, University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandExosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of QueenslandAbstract Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. Methods Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. Results A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. Conclusions During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.https://doi.org/10.1186/s12967-021-02999-9PregnancyExosomesmiRNAsInsulin resistanceSkeletal muscle |