Nat Commun.: co-auth.: B.Thorens

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


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.