Carlos Salomon, 1,2 Katherin Scholz-Romero, 1 Suchismita Sarker, 1 Emma Sweeney, 1 Miharu Kobayashi, 1 Paula Correa, 3 Sherri Longo, 1,2 Gregory Duncombe, 1 Murray D. Mitchell, 1,2 Gregory E. Rice, 1,2,3 and Sebastian E. Illanes 1,3 Gestational Diabetes Mellitus Is Associated With Changes in the Concentration and Bioactivity of Placenta-Derived Exosomes in Maternal Circulation Across Gestation Diabetes 2016;65:598–609 | DOI: 10.2337/db15-0966 Although there is significant interest in elucidating the role of placenta-derived exosomes (PdEs) during pregnancy, the exosomal profile in pregnancies com- plicated by gestational diabetes mellitus (GDM) re- mains to be established. The aim of this study was to compare the gestational-age profile of PdEs in ma- ternal plasma of GDM with normal pregnancies and to determine the effect of exosomes on cytokine release from human umbilical vein endothelial cells. A prospec- tive cohort of patients was sampled at three time points during pregnancy for each patient (i.e., 11–14, 22–24, and 32–36 weeks’ gestation). A retrospective stratified study design was used to quantify exosomes present in maternal plasma of normal (n = 13) and GDM (n = 7) pregnancies. Gestational age and pregnancy status were identi fied as signi ficant factors contri- buting to variation in plasma exosome concentration (ANOVA, P < 0.05). Post hoc analyses established that PdE concentration increased during gestation in both normal and GDM pregnancies; however, the increase was signi ficantly greater in GDM ( ∼2.2-fold, ∼1.5-fold, and ∼1.8-fold greater at each gestational age compared with normal pregnancies). Exosomes iso- lated from GDM pregnancies significantly increased the release of proinflammatory cytokines from endo- thelial cells. Although the role of exosomes during GDM remains to be fully elucidated, exosome profiles may be of diagnostic utility for screening asymptomatic populations. Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during preg- nancy (1). Currently, GDM affects ;15% of all pregnan- cies worldwide and its incidence is increasing in parallel with the global increase in obesity and type 2 diabetes (2). Indeed, the incidence of GDM worldwide is predicted to reach 18% when the new International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria are adopted (3). GDM has been associated not only with acute increased risk for complications of pregnancy but also long-term disease risks for both mother and baby. Current management guidelines recommend “universal screening” for GDM at 24–28 weeks of gestation by oral glucose tolerance tests (OGTTs) (4). The recommended interventions of diet, oral hypoglycemic agents, and in- sulin administration have a good impact in perinatal mor- bidity (5). When GDM is diagnosed in the late second or early third trimester of pregnancy, the “pathology” is most likely well established and the possibility to reverse or limit potential adverse effects on perinatal outcomes may be limited (6,7). If an effective first trimester screen- ing test was available, the damage accumulated during the clinically occult phase (i.e., up to 24–28 weeks) may be averted by early intervention. During normal pregnancy, diabetogenic autacoids are released by the placenta and induce insulin resistance and hyperinsulinemia (8). GDM develops in women when in- sulin release fails to compensate for pregnancy-induced 1 Exosome Biology Laboratory, Centre for Clinical Diagnostics, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, Australia 2 Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Ochsner Clinic Foundation, New Orleans, LA 3 Department of Obstetrics and Gynaecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile Corresponding author: Carlos Salomon, c.salomongallo@uq.edu.au. Received 14 July 2015 and accepted 12 December 2015. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-0966/-/DC1. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 598 Diabetes Volume 65, March 2016 METABOLISM Downloaded from http://diabetesjournals.org/diabetes/article-pdf/65/3/598/581924/db150966.pdf by guest on 30 August 2023