Author:
Slieker Roderick C,Donnelly Louise A,Lopez-Noriega Livia,Muniangi-Muhitu Hermine,Akalestou Elina,Sheikh Mahsa,Georgiadou Eleni,Giordano Giuseppe N.,Åkerlund Mikael,Ahlqvist Emma,Ali Ashfaq,Barovic Marko,Bouland Gerard A,Burdet Frédéric,Canouil Mickaël,Dragan Iulian,Elders Petra JM,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,Aly Dina Mansour,Mehl Florence,Marek Diana,Melander Olle,Niknejad Anne,Ottosson Filip,Pavo Imre,Efanov Alexander,Duffin Kevin,Pullen Timothy J.,Simons Kai,Solimena Michele,Suvitaival Tommi,Wretlind Asger,Rossing Peter,Lyssenko Valeriya,Quigley Cristina Legido,Groop Leif,Thorens Bernard,Franks Paul W,Ibberson Mark,Beulens Joline WJ,’t Hart Leen M,Pearson Ewan R,Rutter Guy A
Abstract
ABSTRACTWe have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2;2 were also predictive of disease progression. Of ∼1,300 proteins examined in two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis. This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
Publisher
Cold Spring Harbor Laboratory