TY - JOUR
T1 - Identification of biomarkers for glycaemic deterioration in type 2 diabetes
AU - Slieker, Roderick C.
AU - Donnelly, Louise A.
AU - Akalestou, Elina
AU - Lopez-Noriega, Livia
AU - Melhem, Rana
AU - Güneş, Ayşim
AU - Abou Azar, Frederic
AU - Efanov, Alexander
AU - Georgiadou, Eleni
AU - Muniangi-Muhitu, Hermine
AU - Sheikh, Mahsa
AU - Giordano, Giuseppe N
AU - Åkerlund, Mikael
AU - Ahlqvist, Emma
AU - Ali, Ashfaq
AU - Banasik, Karina
AU - Brunak, Søren
AU - Barovic, Marko
AU - Bouland, Gerard A.
AU - Burdet, Frédéric
AU - Canouil, Mickaël
AU - Dragan, Iulian
AU - Elders, Petra J. M.
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 - Mansour Aly, Dina
AU - Mehl, Florence
AU - Marek, Diana
AU - Melander, Olle
AU - Niknejad, Anne
AU - Ottosson, Filip
AU - Pavo, Imre
AU - Duffin, Kevin
AU - Syed, Samreen K.
AU - Shaw, Janice L.
AU - Cabrera, Over
AU - Pullen, Timothy J.
AU - Simons, Kai
AU - Solimena, Michele
AU - Suvitaival, Tommi
AU - Wretlind, Asger
AU - Rossing, Peter
AU - Lyssenko, Valeriya
AU - Legido Quigley, Cristina
AU - Groop, Leif
AU - Thorens, Bernard
AU - Franks, Paul W.
AU - Lim, Gareth E.
AU - Estall, Jennifer
AU - Ibberson, Mark
AU - Beulens, Joline W. J.
AU - 't Hart, Leen M.
AU - Pearson, Ewan R.
AU - Rutter, Guy A.
N1 - Funding Information:
The ANDIS study was financed by Swedish governmental funding of clinical research (ALF), the Faculty of Medicine at Lund University, the Swedish Research Council project grant no. 2020-02191 and strategic research area grant no. 2009-1039 (EXODIAB), from the Swedish Foundation for Strategic Research IRC15-0067 (LUDC-IRC) and Vinnova Swelife. E.R.P. holds a Wellcome Trust New Investigator Award (102820/Z/13/Z). G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), an Experimental Challenge Grant (DIVA, MR/L02036X/1), a Diabetes UK Project grant (BDA16/0005485) and Innovation Canada for a John R Evans Leader Award. G.E.L. was supported by a CIHR Project Grant (PJT-153144) and holds the Canada Research Chair in Adipocyte Development. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement no. 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI), under contract no. 16.0097. Va.G. is supported by the Icelandic Research Fund (grant no. 184845-051). The Hoorn DCS cohort was supported by grants from the Netherlands Organisation for Health Research and Development (113102006, 459001015). J.E. is supported by the CIHR (PJT-168853).
Copyright:
© 2023. The Author(s).
PY - 2023/5/3
Y1 - 2023/5/3
N2 - 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.
AB - 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.
KW - Mice
KW - Animals
KW - Male
KW - Diabetes Mellitus, Type 2/metabolism
KW - Blood Glucose/metabolism
KW - Islets of Langerhans/metabolism
KW - Insulin/metabolism
KW - Lipids
KW - Biomarkers/metabolism
KW - Cell Adhesion Molecules/metabolism
KW - Extracellular Matrix Proteins/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85158018722&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-38148-7
DO - 10.1038/s41467-023-38148-7
M3 - Article
C2 - 37137910
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 2533
ER -
