Slieker, Rocerick C, Donnelly, Louise A, Jennings, Lori, Hart, Leen M, Pearson, Ewan R and Rutter, Guy A (2022) Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study. https://www.medrxiv.org/content/10.1101/2021.04.22.21255625v1.

Abstract

We have deployed a multiomics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteomics. A Cox regression analysis for correlation with time-to-insulin in 5,953 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2:2 were also predictive of disease progression. Of ~1,300 proteins examined in DCS and GoDARTS, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were positively correlated with progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis, This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential diagnostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Item Type:	Article
Date Deposited:	21 Sep 2022 00:45
Last Modified:	21 Sep 2022 00:45
URI:	https://oak.novartis.com/id/eprint/44523