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Slieker, R.C.; Donnelly, L.A.; Akalestou, E.; Lopez-Noriega, L.; Melhem, R.; Günes, A.; ... ; Rutter, G.A. (2023)

Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Article / Letter to editor
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...Show more 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.
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All authors
Slieker, R.C.; Donnelly, L.A.; Akalestou, E.; Lopez-Noriega, L.; Melhem, R.; Günes, A.; Abou Azar, F.; Efanov, A.; Georgiadou, E.; Muniangi-Muhitu, H.; Sheikh, M.; Giordano, G.N.; Åkerlund, M.; Ahlqvist, E.; Ali, A.; Banasik, K.; Brunak, S.; Barovic, M.; Bouland, G.A.; Burdet, F.; Canouil, M.; Dragan, I.; Elders, P.J.M.; Fernandez, C.; Festa, A.; Fitipaldi, H.; Froguel, P.; Gudmundsdottir, V.; Gudnason, V.; Gerl, M.J.; Heijden, A.A. van der; Jennings, L.L.; Hansen, M.K.; Kim, M.; Leclerc, I.; Klose, C.; Kuznetsov, D.; Aly, D.M.; Mehl, F.; Marek, D.; Melander, O.; Niknejad, A.; Ottosson, F.; Pavo, I.; Duffin, K.; Syed, S.K.; Shaw, J.L.; Cabrera, O.; Pullen, T.J.; Simons, K.; Solimena, M.; Suvitaival, T.; Wretlind, A.; Rossing, P.; Lyssenko, V.; Quigley, C.L.; Groop, L.; Thorens, B.; Franks, P.W.; Lim, G.E.; Estall, J.; Ibberson, M.; Beulens, J.W.J.; Hart, L.M.; Pearson, E.R.; Rutter, G.A.
Date
2023-05-03
Journal
Nature Communications
Volume
14
Issue
1
DOI
doi:10.1038/s41467-023-38148-7
Link
https://www.nature.com/articles/s41467-023-38148-7