학술논문
Identification of biomarkers for glycaemic deterioration in type 2 diabetes
Document Type
article
Author
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
Source
Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)
Subject
Language
English
ISSN
2041-1723
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.