title: Circulating microRNA levels predict residual beta cell function and glycaemic control in children with type 1 diabetes mellitus.
abstract: We aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus.
  
  
  
  Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60 months after diagnosis from a subset of 40 children from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1clevels were measured and insulin-dose adjusted HbA1c(IDAA1c) calculated. miRNAs that at 3 months after diagnosis predicted residual beta cell function and glycaemic control in this subgroup were further validated in the remaining cohort (n = 83). Statistical analysis of miRNA prediction for disease progression was performed by multiple linear regression analysis adjusted for age and sex.
  
  
  
  In the discovery analysis, six miRNAs (hsa-miR-24-3p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-301a-3p and hsa-miR-375) at 3 months correlated with residual beta cell function 6-12 months after diagnosis. Stimulated C-peptide at 12 months was predicted by hsa-miR-197-3p at 3 months (p = 0.034). A doubling of this miRNA level corresponded to a sixfold higher stimulated C-peptide level. In addition, a doubling of hsa-miR-24-3p and hsa-miR-146a-5p levels at 3 months corresponded to a 4.2% (p < 0.014) and 3.5% (p < 0.022) lower IDAA1cvalue at 12 months. Analysis of the remaining cohort confirmed the initial finding for hsa-miR-197-3p (p = 0.018). The target genes for the six miRNAs revealed significant enrichment for pathways related to gonadotropin-releasing hormone receptor and angiogenesis pathways.
  
  
  
  The miRNA hsa-miR-197-3p at 3 months was the strongest predictor of residual beta cell function 1 year after diagnosis in children with type 1 diabetes mellitus.
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Nasim
authors.initials: N
authors.lastname: Samandari
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.|Center for Non-coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Aashiq H
authors.initials: AH
authors.lastname: Mirza
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Simranjeet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Statistics, University of Southern Denmark, Odense, Denmark.
authors.forename: Philip
authors.initials: P
authors.lastname: Hougaard
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Siri
authors.initials: S
authors.lastname: Fredheim
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark. flemming.pociot.01@regionh.dk.|Center for Non-coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark. flemming.pociot.01@regionh.dk.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. flemming.pociot.01@regionh.dk.
authors.forename: Flemming
authors.identifier: 0000-0003-3274-5448
authors.initials: F
authors.lastname: Pociot
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011446:Prospective Studies
chemical_list: D001786:Blood Glucose; C542542:MIRN146 microRNA, human; C554846:MIRN194 microRNA, human; C543845:MIRN24 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs
keywords: Biomarkers; Children; Residual beta cell function; miRNA