Nat Commun. 2023 May 3;14(1):2533. doi: 10.1038/s41467-023-38148-7.
Identification of biomarkers for glycaemic deterioration in type 2 diabetes
Roderick C Slieker # 1 2, Louise A Donnelly # 3, Elina Akalestou # 4, Livia Lopez-Noriega 4, Rana Melhem 5, Ayşim Güneş 6, Frederic Abou Azar 5, Alexander Efanov 7, Eleni Georgiadou 4, Hermine Muniangi-Muhitu 4, Mahsa Sheikh 4, Giuseppe N Giordano 8, Mikael Åkerlund 8, Emma Ahlqvist 8, Ashfaq Ali 9, Karina Banasik 10, Søren Brunak 10, Marko Barovic 11, Gerard A Bouland 2, Frédéric Burdet 12, Mickaël Canouil 13, Iulian Dragan 12, Petra J M Elders 14, Celine Fernandez 8, Andreas Festa 15 16, Hugo Fitipaldi 8, Phillippe Froguel 13 17, Valborg Gudmundsdottir 18 19, Vilmundur Gudnason 18 19, Mathias J Gerl 20, Amber A van der Heijden 14, Lori L Jennings 21, Michael K Hansen 22, Min Kim 9 23, Isabelle Leclerc 4 5, Christian Klose 20, Dmitry Kuznetsov 12, Dina Mansour Aly 8, Florence Mehl 12, Diana Marek 12, Olle Melander 8, Anne Niknejad 12, Filip Ottosson 8 24, Imre Pavo 15, Kevin Duffin 7, Samreen K Syed 7, Janice L Shaw 7, Over Cabrera 7, Timothy J Pullen 4 25, Kai Simons 20, Michele Solimena 11 26, Tommi Suvitaival 9, Asger Wretlind 9, Peter Rossing 9 27, Valeriya Lyssenko 28 29, Cristina Legido Quigley 9 23, Leif Groop 8 30, Bernard Thorens 31, Paul W Franks 8 32, Gareth E Lim 5, Jennifer Estall 6, Mark Ibberson 12, Joline W J Beulens 1 33, Leen M ‘t Hart 34 35 36, Ewan R Pearson 37, Guy A Rutter 38 39 40Affiliations expand
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.
- PMID: 37137910
- DOI: 10.1038/s41467-023-38148-7