Nature Communications (May 2023)
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,
- Guy A. Rutter
Affiliations
- Roderick C. Slieker
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
- Louise A. Donnelly
- Population Health & Genomics, School of Medicine, University of Dundee
- Elina Akalestou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Livia Lopez-Noriega
- Section of Cell Biology and Functional Genomics, 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
- Lilly Research Laboratories, Eli Lilly and Company
- Eleni Georgiadou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Hermine Muniangi-Muhitu
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Mahsa Sheikh
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
- Giuseppe N. Giordano
- Department of Clinical Sciences, Lund University
- Mikael Åkerlund
- Department of Clinical Sciences, Lund University
- Emma Ahlqvist
- Department of Clinical Sciences, 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
- Department of Cell and Chemical Biology, Leiden University Medical Center
- Frédéric Burdet
- Vital-IT Group, SIB Swiss Institute of Bioinformatics
- Mickaël Canouil
- INSERM U1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital
- Iulian Dragan
- Vital-IT Group, SIB Swiss Institute of Bioinformatics
- Petra J. M. Elders
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC–location VUmc
- Celine Fernandez
- Department of Clinical Sciences, Lund University
- Andreas Festa
- Eli Lilly Regional Operations GmbH
- Hugo Fitipaldi
- Department of Clinical Sciences, Lund University
- Phillippe Froguel
- INSERM U1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital
- Valborg Gudmundsdottir
- Faculty of Medicine, University of Iceland
- Vilmundur Gudnason
- Faculty of Medicine, University of Iceland
- Mathias J. Gerl
- Lipotype GmbH
- Amber A. van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC–location VUmc
- Lori L. Jennings
- Novartis Institutes for Biomedical Research
- Michael K. Hansen
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development
- Min Kim
- Steno Diabetes Center Copenhagen
- Isabelle Leclerc
- Section of Cell Biology and Functional Genomics, 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
- Department of Clinical Sciences, Lund University
- Florence Mehl
- Vital-IT Group, SIB Swiss Institute of Bioinformatics
- Diana Marek
- Vital-IT Group, SIB Swiss Institute of Bioinformatics
- Olle Melander
- Department of Clinical Sciences, Lund University
- Anne Niknejad
- Vital-IT Group, SIB Swiss Institute of Bioinformatics
- Filip Ottosson
- Department of Clinical Sciences, Lund University
- Imre Pavo
- Eli Lilly Regional Operations GmbH
- Kevin Duffin
- Lilly Research Laboratories, Eli Lilly and Company
- Samreen K. Syed
- Lilly Research Laboratories, Eli Lilly and Company
- Janice L. Shaw
- Lilly Research Laboratories, Eli Lilly and Company
- Over Cabrera
- Lilly Research Laboratories, Eli Lilly and Company
- Timothy J. Pullen
- Section of Cell Biology and Functional Genomics, 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
- Department of Clinical Science, Center for Diabetes Research, University of Bergen
- Cristina Legido Quigley
- Steno Diabetes Center Copenhagen
- Leif Groop
- Department of Clinical Sciences, Lund University
- Bernard Thorens
- Center for Integrative Genomics, University of Lausanne
- Paul W. Franks
- Department of Clinical Sciences, 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
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
- Leen M ’t Hart
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC
- Ewan R. Pearson
- Population Health & Genomics, School of Medicine, University of Dundee
- Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London
- DOI
- https://doi.org/10.1038/s41467-023-38148-7
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
