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Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study
medRxiv - Endocrinology Pub Date : 2021-04-24 , DOI: 10.1101/2021.04.22.21255625
Roderick C Slieker , Louise A Donnelly , Livia Lopez-Noriega , Hermine Muniangi-Muhitu , Elina Akalestou , Mahsa Sheikh , Eleni Georgiadou , Giuseppe N. Giordano , Mikael Åkerlund , Emma Ahlqvist , Ashfaq Ali , Marko Barovic , Gerard A Bouland , Frédéric Burdet , Mickaël Canouil , Iulian Dragan , Petra JM Elders , Celine Fernandez , Andreas Festa , Hugo Fitipaldi , Phillippe Froguel , Valborg Gudmundsdottir , Vilmundur Gudnason , Mathias J. Gerl , Amber A van der Heijden , Lori L Jennings , Michael K. Hansen , Min Kim , Isabelle Leclerc , Christian Klose , Dmitry Kuznetsov , Dina Mansour Aly , Florence Mehl , Diana Marek , Olle Melander , Anne Niknejad , Filip Ottosson , Imre Pavo , Alexander Efanov , Kevin Duffin , Timothy J. Pullen , Kai Simons , Michele Solimena , Tommi Suvitaival , Asger Wretlind , Peter Rossing , Valeriya Lyssenko , Cristina Legido Quigley , Leif Groop , Bernard Thorens , Paul W Franks , Mark Ibberson , Joline WJ Beulens , Leen M ’t Hart , Ewan R Pearson , Guy A Rutter

We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 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 two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. 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 IL-18R 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 prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

中文翻译:

IMI RHAPSODY研究用于2型糖尿病血糖恶化的新型生物标志物

我们已经对现有2型糖尿病的大批患者部署了多组学方法,以鉴定跨三种分子类别,代谢产物,脂质和蛋白质的疾病进展的生物标志物。在DCS,ANDIS和GoDARTS队列中的2,973例患者中,对与胰岛素需求时间相关的Cox回归分析确定高瓜氨酸,异亮氨酸和2-氨基己二酸,以及胆汁酸,糖胆酸和牛磺胆酸,可预示更迅速的恶化。八种三酰甘油种类的水平升高和鞘磷脂SM 42:2; 2的水平降低也预示了疾病的进展。在两个队列中检查的大约1,300种蛋白质中,GDF-15 / MIC1,IL-18RA,CRELD1,NogoR,FAS和ENPP7的水平与更快的进展相关,而SMAC / DIABLO,COTL1,SPOCK1和HEMK2预测较低的进展率。令人惊讶的是,在外部复制人​​群中,鉴定出的蛋白质和脂质也与糖尿病的发病率和患病率相关。NogoR / RTN4R在疾病补偿中起着重要的作用,它改善了高脂喂养小鼠的葡萄糖耐量,并倾向于改善肝细胞中的胰岛素信号传导,而IL-18R则在体外拮抗了炎症性IL-18向核因子kappa-B的传导。相反,高的NogoR水平导致胰岛细胞凋亡。因此,这种全面的,多学科的方法可以识别具有潜在预后效用的新型生物标志物,为新的疾病机制提供证据,并可以识别出减缓糖尿病进展的潜在治疗途径。在外部复制人​​群中,鉴定出的蛋白质和脂质也与糖尿病的发生率和患病率相关。NogoR / RTN4R在疾病补偿中起着重要的作用,它改善了高脂喂养小鼠的葡萄糖耐量,并倾向于改善肝细胞中的胰岛素信号传导,而IL-18R则在体外拮抗了炎症性IL-18信号传导给核因子kappa-B。相反,高的NogoR水平导致胰岛细胞凋亡。因此,这种全面的,多学科的方法可以识别具有潜在预后效用的新型生物标志物,为新的疾病机制提供证据,并可以识别出减缓糖尿病进展的潜在治疗途径。在外部复制人​​群中,鉴定出的蛋白质和脂质也与糖尿病的发生率和患病率相关。NogoR / RTN4R在疾病补偿中起着重要的作用,它改善了高脂喂养小鼠的葡萄糖耐量,并倾向于改善肝细胞中的胰岛素信号传导,而IL-18R则在体外拮抗了炎症性IL-18信号传导给核因子kappa-B。相反,高的NogoR水平导致胰岛细胞凋亡。因此,这种全面的,多学科的方法可以识别具有潜在预后效用的新型生物标志物,为新的疾病机制提供证据,并可以识别出减缓糖尿病进展的潜在治疗途径。NogoR / RTN4R改善了高脂喂养小鼠的葡萄糖耐量,并倾向于改善肝细胞中的胰岛素信号传导,而IL-18R在体外拮抗了炎症性IL-18信号向核因子kappa-B的传递。相反,高的NogoR水平导致胰岛细胞凋亡。因此,这种全面的,多学科的方法可以识别具有潜在预后效用的新型生物标志物,为新的疾病机制提供证据,并可以识别出减缓糖尿病进展的潜在治疗途径。NogoR / RTN4R改善了高脂喂养小鼠的葡萄糖耐量,并倾向于改善肝细胞中的胰岛素信号传导,而IL-18R在体外拮抗了炎症性IL-18信号向核因子kappa-B的传递。相反,高的NogoR水平导致胰岛细胞凋亡。因此,这种全面的,多学科的方法可以识别具有潜在预后效用的新型生物标志物,为新的疾病机制提供证据,并可以识别出减缓糖尿病进展的潜在治疗途径。
更新日期:2021-04-26
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