TY - RPRT TI - Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study AU - Slieker, Roderick C AU - Donnelly, Louise A AU - Lopez-Noriega, Livia AU - Muniangi-Muhitu, Hermine AU - Akalestou, Elina AU - Sheikh, Mahsa AU - Georgiadou, Eleni AU - Giordano, Giuseppe N. AU - Åkerlund, Mikael AU - Ahlqvist, Emma AU - Ali, Ashfaq AU - Barovic, Marko AU - Bouland, Gerard A AU - Burdet, Frédéric AU - Canouil, Mickaël AU - Dragan, Iulian AU - Elders, Petra JM AU - Fernandez, Celine AU - Festa, Andreas AU - Fitipaldi, Hugo AU - Froguel, Phillippe AU - Gudmundsdottir, Valborg AU - Gudnason, Vilmundur AU - Gerl, Mathias J. AU - van der Heijden, Amber A AU - Jennings, Lori L AU - Hansen, Michael K. AU - Kim, Min AU - Leclerc, Isabelle AU - Klose, Christian AU - Kuznetsov, Dmitry AU - Aly, Dina Mansour AU - Mehl, Florence AU - Marek, Diana AU - Melander, Olle AU - Niknejad, Anne AU - Ottosson, Filip AU - Pavo, Imre AU - Efanov, Alexander AU - Duffin, Kevin AU - Pullen, Timothy J. AU - Simons, Kai AU - Solimena, Michele AU - Suvitaival, Tommi AU - Wretlind, Asger AU - Rossing, Peter AU - Lyssenko, Valeriya AU - Quigley, Cristina Legido AU - Groop, Leif AU - Thorens, Bernard AU - Franks, Paul W AU - Ibberson, Mark AU - Beulens, Joline WJ AU - ’t Hart, Leen M AU - Pearson, Ewan R AU - Rutter, Guy A AB - ABSTRACT We 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. DA - 2021/04/24/ PY - 2021 DP - DOI.org (Crossref) LA - en M3 - preprint PB - Endocrinology (including Diabetes Mellitus and Metabolic Disease) ST - Novel biomarkers for glycaemic deterioration in type 2 diabetes UR - http://medrxiv.org/lookup/doi/10.1101/2021.04.22.21255625 Y2 - 2021/11/01/13:25:31 KW - WP3 KW - WP4 KW - WP5 KW - WP6 ER -