Identification of biomarkers for glycaemic deterioration in type 2 diabetes
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Identification of biomarkers for glycaemic deterioration in type 2 diabetes. / 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.
In: Nature Communications, Vol. 14, 2533, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - © 2023. The Author(s).
PY - 2023
Y1 - 2023
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
U2 - 10.1038/s41467-023-38148-7
DO - 10.1038/s41467-023-38148-7
M3 - Journal article
C2 - 37137910
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2533
ER -
ID: 346589051