Profiling circulating microRNAs in pregnancies complicated by type 1 diabetes, type 2 diabetes and gestational diabetes mellitus

Abstract

Maternal diabetes is associated with complications for both mother and child. Mothers have an increased risk of hypertension and caesarean section, while the risk of macrosomia, hypoglycaemia, respiratory distress syndrome, preterm delivery, malformations, and mortality is increased in children. Moreover, both mothers and children have a life-long risk of developing type 2 diabetes (T2DM) and cardiovascular disorders in future. Evidence suggests that women with pregestational type 1 diabetes (T1DM) and T2DM have a greater risk of complications compared to women with gestational diabetes mellitus (GDM), although the mechanisms that link maternal diabetes type with adverse outcomes are not elucidated. In recent years, epigenetic mechanisms, such as microRNAs (miRNAs), have emerged as key players in the pathophysiology of pregnancy complications. The aim of this study was to assess the effect of maternal diabetes type on circulating miRNA expression. Demographic information and serum were obtained from pregnant women with T1DM (n=6), T2DM (n=26), GDM (n=17) and normoglycaemia (n=24) at 16-27 weeks of gestation. C-peptide, total and high molecular weight (HMW) adiponectin, triglycerides and C-reactive protein (CRP) concentrations were measured using enzyme-linked immunosorbent assays. Serum miRNAs were profiled using the Human Serum/Plasma miScript miRNA PCR array (n=4 per group). Women with T2DM (p=0.04) and GDM (p=0.015) were older than women with T1DM. Glucose concentrations were higher in women with maternal diabetes compared to normoglycaemia (p<0.001), and women with T1DM (P=0.039) and T2DM (p=0.019) had higher levels of glycated haemoglobin than women with GDM. Pulse rate was higher in women with T2DM (p=0.003) and GDM (p=0.003) compared to women with normoglycaemia. All metabolic parameters varied significantly across the four groups. Pairwise analysis showed higher levels of insulin in women with T1DM (p=0.008), T2DM (p=0.013) and GDM (p=0.014) compared to normoglycaemia. C-peptide levels were higher in women with GDM compared to normoglycaemia (p=0.010) and T1DM (p=0.051). Total adiponectin concentrations were lower in women with T2DM (p=0.005) and GDM (p=0.030) compared to normoglycaemia, while HMW adiponectin concentrations were lower in women with T2DM (p=0.038) and GDM (p=0.052) compared to T1DM. Triglyceride levels were higher in women with GDM compared to controls (p=0.030), while CRP levels were higher in women with T2DM compared to normoglycaemia (p=0.008).The expression of miRNAs varied between groups, with significance observed for miR-19b-3p (9.8-fold; p=0.033) in women with GDM, miR-20a-5p (4.5-fold; p=0.047) in T1DM, and miR-29a-3p (1.8-fold; p=0.002) in T2DM compared to women with normoglycaemia. Bioinformatic analysis of miRNA gene targets showed that the forkhead box protein O1 (FOXO1) signalling and miRNAs in cancer pathways were common to all three miRNAs, while 15 KEGG pathways were common between miR-20a-5p and miR-29a-3p, and 27 pathways were unique to specific miRNAs. We identified miRNA signatures associated with T1DM, T2DM and GDM, which may contribute towards advancing our knowledge and understanding of mechanisms underlying the different types of diabetes in pregnancy. Further exploration of these miRNA signatures and their association with pregnancy outcomes, may offer potential as biomarkers to predict adverse outcomes.