학술논문
Identification of biomarkers for glycaemic deterioration in type 2 diabetes
Document Type
Author
Slieker, Roderick C; Donnelly, Louise A; Akalestou, Elina; Lopez-Noriega, Livia; Melhem, Rana; Güneş, Ayşim; Abou Azar, Frederic; Efanov, Alexander; Georgiadou, Eleni; Muniangi-Muhitu, Hermine; Sheikh, Mahsa; Giordano, Giuseppe N; Åkerlund, Mikael; Ahlqvist, Emma; Ali, Ashfaq; Banasik, Karina; Brunak, Søren; Barovic, Marko; Bouland, Gerard A; Burdet, Frédéric; Canouil, Mickaël; Dragan, Iulian; Elders, Petra J M; Fernandez, Celine; Festa, Andreas; Fitipaldi, Hugo; Froguel, Phillippe; Gudmundsdottir, Valborg; Gudnason, Vilmundur; Gerl, Mathias J; van der Heijden, Amber A; Jennings, Lori L; Hansen, Michael K; Kim, Min; Leclerc, Isabelle; Klose, Christian; Kuznetsov, Dmitry; Mansour Aly, Dina; Mehl, Florence; Marek, Diana; Melander, Olle; Niknejad, Anne; Ottosson, Filip; Pavo, Imre; Duffin, Kevin; Syed, Samreen K; Shaw, Janice L; Cabrera, Over; Pullen, Timothy J; Simons, Kai; Solimena, Michele; Suvitaival, Tommi; Wretlind, Asger; Rossing, Peter; Lyssenko, Valeriya; Legido Quigley, Cristina; Groop, Leif; Thorens, Bernard; Franks, Paul W; Lim, Gareth E; Estall, Jennifer; Ibberson, Mark; Beulens, Joline W J; 't Hart, Leen M; Pearson, Ewan R; Rutter, Guy A
Source
Nature Communications EXODIAB: Excellence of Diabetes Research in Sweden EpiHealth: Epidemiology for Health eSSENCE: The e-Science Collaboration MultiPark: Multidisciplinary research focused on Parkinson´s disease. 14:1-18
Subject
Language
English
ISSN
2041-1723
Abstract
We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.