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.
Original language | English |
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Article number | 2533 |
Journal | Nature Communications |
Volume | 14 |
Number of pages | 18 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
© 2023. The Author(s).Keywords
- Mice
- Animals
- Male
- Diabetes Mellitus, Type 2/metabolism
- Blood Glucose/metabolism
- Islets of Langerhans/metabolism
- Insulin/metabolism
- Lipids
- Biomarkers/metabolism
- Cell Adhesion Molecules/metabolism
- Extracellular Matrix Proteins/metabolism