Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus

Journal of Translational Medicine

Alexis Shub¹  Elizabeth A. McCarthy¹  Martha Lappas¹  Dominic Guanzon²  Carlos Palma²  Gregory Rice²  Gregory Duncombe²  Nanthini Jayabalan²  Andrew Lai²  Priyakshi Kalita de Croft²  Soumyalekshmi Nair²  Katherin Scholz-Romero³  Carlos Salomon³  Valeska Ormazabal⁴  Emilio Diaz⁵  Eduard Gratacós⁶  Fátima Crispi⁶  Jezid Miranda⁶  H. David McIntyre⁷ 

[1] Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia;Mercy Hospital for Women, 163 Studley Road, 3084, Heidelberg, VIC, Australia;Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, 4029, Herston, QLD, Australia;Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, 4029, Herston, QLD, Australia;Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile;Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile;Faculty of Medicine, Department of Obstetrics and Gynaecology, University of Concepcion, Concepción, Chile;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), Barcelona, Spain;Mater Research, Faculty of Medicine, University of Queensland, Mater Health, South Brisbane, Australia;

关键词: Pregnancy;    Exosomes;    miRNAs;    Insulin resistance;    Skeletal muscle;   

DOI  :  10.1186/s12967-021-02999-9

来源: Springer

【 摘 要 】

BackgroundGestational 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.MethodsDiscovery: 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.ResultsA 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.ConclusionsDuring 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.

【 授权许可】

CC BY