Testa Roberto, Vanhooren Valerie, Bonfigli Anna Rita, Boemi Massimo, Olivieri Fabiola, Ceriello Antonio, Genovese Stefano, Spazzafumo Liana, Borelli Vincenzo, Bacalini Maria Giulia, Salvioli Stefano, Garagnani Paolo, Dewaele Sylviane, Libert Claude, Franceschi Claudio
Experimental models in Clinical Pathology, Italian National Research Center on Aging (INRCA), Ancona, 60127, Italy.
VIB Inflammation Research Center, Technologiepark 927, B-9052, Ghent, Belgium; Department of Molecular Biology, Ghent University, Technologiepark 927, B-9052, Ghent, Belgium.
PLoS One. 2015 Mar 20;10(3):e0119983. doi: 10.1371/journal.pone.0119983. eCollection 2015.
Glycosylation, i.e the enzymatic addition of oligosaccharides (or glycans) to proteins and lipids, known as glycosylation, is one of the most common co-/posttranslational modifications of proteins. Many important biological roles of glycoproteins are modulated by N-linked oligosaccharides. As glucose levels can affect the pathways leading to glycosylation of proteins, we investigated whether metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), pathological conditions characterized by altered glucose levels, are associated with specific modifications in serum N-glycome.
We enrolled in the study 562 patients with Type 2 Diabetes Mellitus (T2DM) (mean age 65.6±8.2 years) and 599 healthy control subjects (CTRs) (mean age, 58.5±12.4 years). N-glycome was evaluated in serum glycoproteins.
We found significant changes in N-glycan composition in the sera of T2DM patients. In particular, α(1,6)-linked arm monogalactosylated, core-fucosylated diantennary N-glycans (NG1(6)A2F) were significantly reduced in T2DM compared with CTR subjects. Importantly, they were equally reduced in diabetic patients with and without complications (P<0.001) compared with CTRs. Macro vascular-complications were found to be related with decreased levels of NG1(6)A2F. In addition, NG1(6)A2F and NG1(3)A2F, identifying, respectively, monogalactosylated N-glycans with α(1,6)- and α(1,3)-antennary galactosylation, resulted strongly correlated with most MS parameters. The plasmatic levels of these two glycans were lower in T2DM as compared to healthy controls, and even lower in patients with complications and MS, that is the extreme "unhealthy" phenotype (T2DM+ with MS).
Imbalance of glycosyltransferases, glycosidases and sugar nucleotide donor levels is able to cause the structural changes evidenced by our findings. Serum N-glycan profiles are thus sensitive to the presence of diabetes and MS. Serum N-glycan levels could therefore provide a non-invasive alternative marker for T2DM and MS.
糖基化，即将寡糖（或聚糖）酶促添加到蛋白质和脂质上的过程，是蛋白质最常见的共翻译/翻译后修饰之一。糖蛋白的许多重要生物学作用受N-连接寡糖调节。由于葡萄糖水平会影响导致蛋白质糖基化的途径，我们研究了代谢综合征（MS）和2型糖尿病（T2DM）这两种以葡萄糖水平改变为特征的病理状况是否与血清N-聚糖组的特定修饰有关。
我们招募了562例2型糖尿病（T2DM）患者（平均年龄65.6±8.2岁）和599例健康对照者（CTR）（平均年龄58.5±12.4岁）。对血清糖蛋白中的N-聚糖组进行评估。
我们发现T2DM患者血清中的N-聚糖组成有显著变化。特别是，与CTR受试者相比，T2DM患者中α(1,6)连接臂单半乳糖基化、核心岩藻糖基化的二天线N-聚糖（NG1(6)A2F）显著减少。重要的是，与CTR相比，有并发症和无并发症的糖尿病患者中其减少程度相同（P<0.001）。发现大血管并发症与NG1(6)A2F水平降低有关。此外，分别鉴定具有α(1,6)-和α(1,3)-天线半乳糖基化的单半乳糖基化N-聚糖的NG1(6)A2F和NG1(3)A2F与大多数MS参数密切相关。与健康对照相比，这两种聚糖的血浆水平在T2DM患者中较低，在有并发症和MS的患者中更低，即极端“不健康”表型（伴有MS的T2DM+）。
糖基转移酶、糖苷酶和糖核苷酸供体水平的失衡能够导致我们的研究结果所证明的结构变化。因此，血清N-聚糖谱对糖尿病和MS的存在敏感。血清N-聚糖水平因此可为T2DM和MS提供一种非侵入性替代标志物。
