Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A. Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J. M. Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J. Gerl, Amber A. van der Heijden, Lori L. Jennings, Michael K. Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W. Franks, Gareth E. Lim, Jennifer Estall, Mark Ibberson, Joline W. J. Beulens, Leen M ’t Hart (), Ewan R. Pearson () and Guy A. Rutter ()
Additional contact information
Roderick C. Slieker: Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
Louise A. Donnelly: University of Dundee
Elina Akalestou: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Livia Lopez-Noriega: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Rana Melhem: CHUM Research Centre and University of Montreal
Ayşim Güneş: IRCM and University of Montreal
Frederic Abou Azar: CHUM Research Centre and University of Montreal
Alexander Efanov: Eli Lilly and Company
Eleni Georgiadou: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Hermine Muniangi-Muhitu: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Mahsa Sheikh: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Giuseppe N. Giordano: Lund University
Mikael Åkerlund: Lund University
Emma Ahlqvist: Lund University
Ashfaq Ali: Steno Diabetes Center Copenhagen
Karina Banasik: Novo Nordisk Foundation Center for Protein Research
Søren Brunak: Novo Nordisk Foundation Center for Protein Research
Marko Barovic: Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Medical Faculty
Gerard A. Bouland: Leiden University Medical Center
Frédéric Burdet: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Mickaël Canouil: Lille University Hospital
Iulian Dragan: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Petra J. M. Elders: Amsterdam Public Health Research Institute, Amsterdam UMC–location VUmc
Celine Fernandez: Lund University
Andreas Festa: Eli Lilly Regional Operations GmbH
Hugo Fitipaldi: Lund University
Phillippe Froguel: Lille University Hospital
Valborg Gudmundsdottir: University of Iceland
Vilmundur Gudnason: University of Iceland
Mathias J. Gerl: Lipotype GmbH
Amber A. van der Heijden: Amsterdam Public Health Research Institute, Amsterdam UMC–location VUmc
Lori L. Jennings: Novartis Institutes for Biomedical Research
Michael K. Hansen: Janssen Research & Development
Min Kim: Steno Diabetes Center Copenhagen
Isabelle Leclerc: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Christian Klose: Lipotype GmbH
Dmitry Kuznetsov: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Dina Mansour Aly: Lund University
Florence Mehl: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Diana Marek: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Olle Melander: Lund University
Anne Niknejad: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Filip Ottosson: Lund University
Imre Pavo: Eli Lilly Regional Operations GmbH
Kevin Duffin: Eli Lilly and Company
Samreen K. Syed: Eli Lilly and Company
Janice L. Shaw: Eli Lilly and Company
Over Cabrera: Eli Lilly and Company
Timothy J. Pullen: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
Kai Simons: Lipotype GmbH
Michele Solimena: Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Medical Faculty
Tommi Suvitaival: Steno Diabetes Center Copenhagen
Asger Wretlind: Steno Diabetes Center Copenhagen
Peter Rossing: Steno Diabetes Center Copenhagen
Valeriya Lyssenko: University of Bergen
Cristina Legido Quigley: Steno Diabetes Center Copenhagen
Leif Groop: Lund University
Bernard Thorens: University of Lausanne
Paul W. Franks: Lund University
Gareth E. Lim: CHUM Research Centre and University of Montreal
Jennifer Estall: IRCM and University of Montreal
Mark Ibberson: Vital-IT Group, SIB Swiss Institute of Bioinformatics
Joline W. J. Beulens: Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
Leen M ’t Hart: Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
Ewan R. Pearson: University of Dundee
Guy A. Rutter: Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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 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.

Date: 2023
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Citations: View citations in EconPapers (1)

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DOI: 10.1038/s41467-023-38148-7

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