Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC, Amsterdam, the Netherlands.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Nat Commun. 2023 May 3;14(1):2533. doi: 10.1038/s41467-023-38148-7.
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.
我们在三个 2 型糖尿病队列中确定了疾病进展的生物标志物，这些队列涵盖了三个分子类别、代谢物、脂质和蛋白质的 2973 个人。同型瓜氨酸、异亮氨酸和 2-氨基己二酸、八种三酰甘油种类以及降低的鞘氨醇 42:2;2 水平可预测向胰岛素需求的更快进展。在两个队列中检查了大约 1300 种蛋白质，GDF15/MIC-1、IL-18Ra、CRELD1、NogoR、FAS 和 ENPP7 的水平与更快的进展相关，而 SMAC/DIABLO、SPOCK1 和 HEMK2 则预测进展速度较慢。在外部复制中，蛋白质和脂质与糖尿病的发病率和患病率相关。NogoR/RTN4R 注射可改善高脂肪喂养雄性小鼠的葡萄糖耐量，但会损害雄性 db/db 小鼠的葡萄糖耐量。高 NogoR 水平导致胰岛细胞凋亡，IL-18R 在体外拮抗炎症性 IL-18 信号向核因子 kappa-B。因此，这种全面的多学科方法确定了具有潜在预后效用的生物标志物，为可能的疾病机制提供了证据，并确定了减缓糖尿病进展的潜在治疗途径。
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