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Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author

Listed:
  • Roderick C. Slieker

    (Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
    Leiden University Medical Center)

  • 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
    LK Stockerau)

  • Hugo Fitipaldi

    (Lund University)

  • Phillippe Froguel

    (Lille University Hospital
    Endocrinology and Metabolism, Imperial College London)

  • Valborg Gudmundsdottir

    (University of Iceland
    Icelandic Heart Association)

  • Vilmundur Gudnason

    (University of Iceland
    Icelandic Heart Association)

  • 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
    Faculty of Life Sciences and Medicines, King’s College London)

  • Isabelle Leclerc

    (Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
    CHUM Research Centre and University of Montreal)

  • 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
    Statens Serum Institut)

  • 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
    Guy’s Campus King’s 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
    University Hospital and Medical Faculty Carl Gustav Carus)

  • Tommi Suvitaival

    (Steno Diabetes Center Copenhagen)

  • Asger Wretlind

    (Steno Diabetes Center Copenhagen)

  • Peter Rossing

    (Steno Diabetes Center Copenhagen
    University of Copenhagen)

  • Valeriya Lyssenko

    (University of Bergen
    Lund University Diabetes Centre, Skåne University Hospital)

  • Cristina Legido Quigley

    (Steno Diabetes Center Copenhagen
    Faculty of Life Sciences and Medicines, King’s College London)

  • Leif Groop

    (Lund University
    Helsinki University)

  • Bernard Thorens

    (University of Lausanne)

  • Paul W. Franks

    (Lund University
    Harvard School of Public Health)

  • 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
    University Medical Center Utrecht)

  • Leen M ’t Hart

    (Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
    Leiden University Medical Center
    Leiden University Medical Center)

  • Ewan R. Pearson

    (University of Dundee)

  • Guy A. Rutter

    (Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
    CHUM Research Centre and University of Montreal
    Nanyang Technological University)

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.

Suggested Citation

  • 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 & Mahs, 2023. "Identification of biomarkers for glycaemic deterioration in type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38148-7
    DOI: 10.1038/s41467-023-38148-7
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    References listed on IDEAS

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    1. Fiona L. Scott & Boguslaw Stec & Cristina Pop & Małgorzata K. Dobaczewska & JeongEun J. Lee & Edward Monosov & Howard Robinson & Guy S. Salvesen & Robert Schwarzenbacher & Stefan J. Riedl, 2009. "The Fas–FADD death domain complex structure unravels signalling by receptor clustering," Nature, Nature, vol. 457(7232), pages 1019-1022, February.
    2. Luca A Lotta & Robert A Scott & Stephen J Sharp & Stephen Burgess & Jian’an Luan & Therese Tillin & Amand F Schmidt & Fumiaki Imamura & Isobel D Stewart & John R B Perry & Luke Marney & Albert Koulman, 2016. "Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis," PLOS Medicine, Public Library of Science, vol. 13(11), pages 1-22, November.
    3. Anthony P. Coll & Michael Chen & Pranali Taskar & Debra Rimmington & Satish Patel & John A. Tadross & Irene Cimino & Ming Yang & Paul Welsh & Samuel Virtue & Deborah A. Goldspink & Emily L. Miedzybrod, 2020. "GDF15 mediates the effects of metformin on body weight and energy balance," Nature, Nature, vol. 578(7795), pages 444-448, February.
    4. Anthony P. Coll & Michael Chen & Pranali Taskar & Debra Rimmington & Satish Patel & John A. Tadross & Irene Cimino & Ming Yang & Paul Welsh & Samuel Virtue & Deborah A. Goldspink & Emily L. Miedzybrod, 2020. "Publisher Correction: GDF15 mediates the effects of metformin on body weight and energy balance," Nature, Nature, vol. 578(7796), pages 24-24, February.
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