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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 and Muniangi-Muhitu, Hermine , et al. (2023) In Nature Communications 14. p.1-18
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mice, Animals, Male, Diabetes Mellitus, Type 2/metabolism, Blood Glucose/metabolism, Islets of Langerhans/metabolism, Insulin/metabolism, Lipids, Biomarkers/metabolism, Cell Adhesion Molecules/metabolism, Extracellular Matrix Proteins/metabolism
in
Nature Communications
volume
14
article number
2533
pages
1 - 18
publisher
Nature Publishing Group
external identifiers
  • scopus:85158018722
  • pmid:37137910
ISSN
2041-1723
DOI
10.1038/s41467-023-38148-7
language
English
LU publication?
yes
additional info
© 2023. The Author(s).
id
51a898b1-315b-4e9c-9a12-57c9db304341
date added to LUP
2023-05-11 15:43:58
date last changed
2024-06-29 03:59:22
@article{51a898b1-315b-4e9c-9a12-57c9db304341,
  abstract     = {{<p>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.</p>}},
  author       = {{Slieker, Roderick C and Donnelly, Louise A and Akalestou, Elina and Lopez-Noriega, Livia and Melhem, Rana and Güneş, Ayşim and Abou Azar, Frederic and Efanov, Alexander and Georgiadou, Eleni and Muniangi-Muhitu, Hermine and Sheikh, Mahsa and Giordano, Giuseppe N and Åkerlund, Mikael and Ahlqvist, Emma and Ali, Ashfaq and Banasik, Karina and Brunak, Søren and Barovic, Marko and Bouland, Gerard A and Burdet, Frédéric and Canouil, Mickaël and Dragan, Iulian and Elders, Petra J M 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 Mansour Aly, Dina and Mehl, Florence and Marek, Diana and Melander, Olle and Niknejad, Anne and Ottosson, Filip and Pavo, Imre and Duffin, Kevin and Syed, Samreen K and Shaw, Janice L and Cabrera, Over and Pullen, Timothy J and Simons, Kai and Solimena, Michele and Suvitaival, Tommi and Wretlind, Asger and Rossing, Peter and Lyssenko, Valeriya and Legido Quigley, Cristina and Groop, Leif and Thorens, Bernard and Franks, Paul W and Lim, Gareth E and Estall, Jennifer and Ibberson, Mark and Beulens, Joline W J and 't Hart, Leen M and Pearson, Ewan R and Rutter, Guy A}},
  issn         = {{2041-1723}},
  keywords     = {{Mice; Animals; Male; Diabetes Mellitus, Type 2/metabolism; Blood Glucose/metabolism; Islets of Langerhans/metabolism; Insulin/metabolism; Lipids; Biomarkers/metabolism; Cell Adhesion Molecules/metabolism; Extracellular Matrix Proteins/metabolism}},
  language     = {{eng}},
  month        = {{05}},
  pages        = {{1--18}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Identification of biomarkers for glycaemic deterioration in type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-38148-7}},
  doi          = {{10.1038/s41467-023-38148-7}},
  volume       = {{14}},
  year         = {{2023}},
}