@report{slieker_novel_2021,
	title = {Novel biomarkers for glycaemic deterioration in type 2 diabetes: an {IMI} {RHAPSODY} study},
	url = {http://medrxiv.org/lookup/doi/10.1101/2021.04.22.21255625},
	shorttitle = {Novel biomarkers for glycaemic deterioration in type 2 diabetes},
	abstract = {{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/{MIC}1, {IL}-18RA, {CRELD}1, {NogoR}, {FAS}, and {ENPP}7 were associated with faster progression, whilst {SMAC}/{DIABLO}, {COTL}1, {SPOCK}1 and {HEMK}2 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}/{RTN}4R 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.},
	institution = {Endocrinology (including Diabetes Mellitus and Metabolic Disease)},
	type = {preprint},
	author = {Slieker, Roderick C and Donnelly, Louise A and Lopez-Noriega, Livia and Muniangi-Muhitu, Hermine and Akalestou, Elina and Sheikh, Mahsa and Georgiadou, Eleni and Giordano, Giuseppe N. and Åkerlund, Mikael and Ahlqvist, Emma and Ali, Ashfaq and Barovic, Marko and Bouland, Gerard A and Burdet, Frédéric and Canouil, Mickaël and Dragan, Iulian and Elders, Petra {JM} and Fernandez, Celine and Festa, Andreas and Fitipaldi, Hugo and Froguel, Phillippe and Gudmundsdottir, Valborg and Gudnason, Vilmundur and Gerl, Mathias J. and van der Heijden, Amber A and Jennings, Lori L and Hansen, Michael K. and Kim, Min and Leclerc, Isabelle and Klose, Christian and Kuznetsov, Dmitry and Aly, Dina Mansour and Mehl, Florence and Marek, Diana and Melander, Olle and Niknejad, Anne and Ottosson, Filip and Pavo, Imre and Efanov, Alexander and Duffin, Kevin and Pullen, Timothy J. and Simons, Kai and Solimena, Michele and Suvitaival, Tommi and Wretlind, Asger and Rossing, Peter and Lyssenko, Valeriya and Quigley, Cristina Legido and Groop, Leif and Thorens, Bernard and Franks, Paul W and Ibberson, Mark and Beulens, Joline {WJ} and ’t Hart, Leen M and Pearson, Ewan R and Rutter, Guy A},
	urldate = {2021-11-01},
	date = {2021-04-24},
	langid = {english},
	doi = {10.1101/2021.04.22.21255625},
	keywords = {{WP}3, {WP}4, {WP}5, {WP}6},
}