title: Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study.
abstract: BACKGROUND
  Advanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development.
  
  
  METHODS
  Participants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8-18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young's modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively.
  
  
  RESULTS
  Levels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young's modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls.
  
  
  CONCLUSIONS
  The results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.
authors.affiliation: Pediatric Department, Oslo University Hospital, Oslo, Norway. martin.heier@medisin.uio.no.|Faculty of Medicine, University of Oslo, Oslo, Norway. martin.heier@medisin.uio.no.|Oslo Diabetes Research Centre, Oslo, Norway. martin.heier@medisin.uio.no.
authors.forename: Martin
authors.initials: M
authors.lastname: Heier
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway. hdismarg@gmail.com.|Oslo Diabetes Research Centre, Oslo, Norway. hdismarg@gmail.com.|Akershus University Hospital, Lørenskog, Norway. hdismarg@gmail.com.
authors.forename: Hanna Dis
authors.initials: HD
authors.lastname: Margeirsdottir
authors.affiliation: Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway. hysefjes@hotmail.com.
authors.forename: Mario
authors.initials: M
authors.lastname: Gaarder
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway. knutsten@gmail.com.|Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway. knutsten@gmail.com.
authors.forename: Knut Haakon
authors.initials: KH
authors.lastname: Stensæth
authors.affiliation: Department of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. UXBRUC@ous-hf.n.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Brunborg
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway. pabusdal@frisurf.no.|Hormone Laboratory, Oslo University Hospital, Oslo, Norway. pabusdal@frisurf.no.
authors.forename: Peter Abusdal
authors.initials: PA
authors.lastname: Torjesen
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway. UXINLJ@ous-hf.no.|Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Oslo, Norway. UXINLJ@ous-hf.no.
authors.forename: Ingebjørg
authors.initials: I
authors.lastname: Seljeflot
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway. k.f.hanssen@medisin.uio.no.|Oslo Diabetes Research Centre, Oslo, Norway. k.f.hanssen@medisin.uio.no.|Department of Endocrinology, Oslo University Hospital, Oslo, Norway. k.f.hanssen@medisin.uio.no.
authors.forename: Kristian Folkvord
authors.initials: KF
authors.lastname: Hanssen
authors.affiliation: Pediatric Department, Oslo University Hospital, Oslo, Norway. knut.dahl-jorgensen@medisin.uio.no.|Faculty of Medicine, University of Oslo, Oslo, Norway. knut.dahl-jorgensen@medisin.uio.no.|Oslo Diabetes Research Centre, Oslo, Norway. knut.dahl-jorgensen@medisin.uio.no.
authors.forename: Knut
authors.initials: K
authors.lastname: Dahl-Jørgensen
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D003925:Diabetic Angiopathies / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D055119:Elastic Modulus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007118:Immunoassay; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D065840:Protective Factors; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood*; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation; D059289:Vascular Stiffness
chemical_list: C000593871:AGER protein, human; D015415:Biomarkers; D000067759:Receptor for Advanced Glycation End Products; D002097:C-Reactive Protein