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