Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes

Keser, Toma; Gornik, Ivan; Vučković, Frano; Selak, Najda; Pavić, Tamara; Lukić, Edita; Gudelj, Ivan; Gašparović, Hrvoje; Biočina, Bojan; Tilin, Therese; Wennerström, Annika; Männistö, Satu; Salomaa, Veikko; Havulinna, Aki S.; Wang, Wei; Wilson, James F.; Charutvedi, Nishi; Perola, Markus; Campbell, Harry; Lauc, Gordan; Gornik, Olga

doi:10.1007/s00125-017-4426-9

Cited by 88 publications

(91 citation statements)

References 23 publications

(23 reference statements)

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“…Identified type 2 diabetes risk allele in European‐descent individuals was associated with an increase in ST6GAL1 expression in islets . This finding further corroborates the hypothesis that highly branched N‐glycans (which are also highly sialylated) are associated with higher risk of developing type 2 diabetes . The study investigating the specific linkage of the sialic acid, as discussed previously, has demonstrated that total plasma protein biantennary N‐glycans with α2,6‐linked sialic acid are increased in type 2 diabetes ; further confirming the potential causal relation between α2,6‐linked sialic acid and type 2 diabetes.…”

Section: Type 2 Diabetessupporting

confidence: 82%

“…Replication cohort comprised individuals with increased levels of HbA1c, incident cases of type 2 diabetes gathered at baseline and controls. Study showed that increased complexity of N-glycan structures (highly branched, galactosylated and sialylated) among total plasma proteins was associated with increased risk of type 2 diabetes development [39]. The same differences were subsequently replicated by the analysis of 820 incident cases of type 2 diabetes in the German part of the .…”

Section: Total Plasma Protein and Igg N-glycan Profiling In Type 2 DImentioning

confidence: 83%

“…Chronic low‐grade inflammation is a common feature in subjects with type 2 diabetes , which could also indicate that the observed changes are reflection of the initial inflammatory process. It is important to stress out that even though in the previously mentioned study total plasma protein N‐glycome that comprises many different glycoproteins was studied, significant differences were observed and enabled identification of individuals at an increased risk of developing this disease . It would be also important to further identify and target specific glycoproteins that are contributing to the observed changes.…”

Section: Type 2 Diabetesmentioning

confidence: 98%

Section: Hexosamine Biosynthesis Pathway and Its Role In Diabetes Thrmentioning

confidence: 99%

“…However, under conditions of hyperglycaemia the percentage of total glucose utilized through the HBP could be enhanced, leading to increased levels of the major product of the HBP, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). This was proposed as one of the mechanisms for the observed increase in plasma levels of the highly branched N-glycan structures in type 1 diabetes patients, type 2 diabetes patients and even healthy people at the increased risk of developing diabetes in the future [39,40,58]. Uridine diphosphate N-acetylglucosamine, a nucleotide-activated sugar, serves as a substrate for different glycosyltransferases in the process of eukaryotic protein N-glycosylation, which occurs when a block of 14 sugars is relocated cotranslationally to specific asparagine residues in the endoplasmic reticulum [32].…”

Section: Hexosamine Biosynthesis Pathway and Its Role In Diabetes Thrmentioning

confidence: 99%

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Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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N‐glycosylation is a ubiquitous protein modification, and N‐glycosylation profiles are emerging as both biomarkers and functional effectors in various types of diabetes. Genome‐wide association studies identified glycosyltransferase genes as candidate causal genes for type 1 and type 2 diabetes. Studies focused on N‐glycosylation changes in type 2 diabetes demonstrated that patients can be distinguished from healthy controls based on N‐glycome composition. In addition, individuals at an increased risk of future disease development could be identified based on N‐glycome profiles. Moreover, accumulating evidence indicates that N‐glycans have a major role in preventing the impairment of glucose‐stimulated insulin secretion by maintaining the glucose transporter in proper orientation, indicating that interindividual variation in protein N‐glycosylation might be a novel risk factor contributing to diabetes development. Defective N‐glycosylation of T cells has been implicated in type 1 diabetes pathogenesis. Furthermore, studies of N‐glycan alterations have successfully been used to identify individuals with rare types of diabetes (such as the HNF1A‐MODY), and also to evaluate functional significance of novel diabetes‐associated mutations. In conclusion, both N‐glycans and glycosyltransferases emerge as potential therapeutic targets in diabetes.

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Section: Type 2 Diabetessupporting

confidence: 82%

Section: Total Plasma Protein and Igg N-glycan Profiling In Type 2 DImentioning

confidence: 83%

Section: Type 2 Diabetesmentioning

confidence: 98%

Section: Hexosamine Biosynthesis Pathway and Its Role In Diabetes Thrmentioning

confidence: 99%

Section: Hexosamine Biosynthesis Pathway and Its Role In Diabetes Thrmentioning

confidence: 99%

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Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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N‐glycome signatures in human plasma: associations with physiology and major diseases

Dotz

Wuhrer

2019

FEBS Letters

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N‐glycome analysis in total plasma or serum yields information about the levels and glycosylation patterns of major plasma glycoproteins, including immunoglobulins, acute‐phase proteins, and apolipoproteins. Until recently, glycomic studies in disease settings largely suffered from small cohort sizes, poor analytical resolution, and poor comparability of results owing to the diversity of analytical techniques. Here, we report on recent advances in high‐throughput mass spectrometry glycomics technology that enabled elucidation of N‐glycome signatures in the plasma of patients with type 2 diabetes, inflammatory bowel disease, or colorectal cancer. Use of this technology revealed both commonalities and differences among disease fingerprints. Moreover, we summarize findings on glycomic signatures associated with age, sex, and body mass index. High‐throughput, high‐resolution glycomics technologies, together with robust data analysis workflows, will advance clinical translation.

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Validation of diagnostic and predictive biomarkers for hereditary angioedema via plasma N‐glycomics

Zhang

Wang

et al. 2021

Clinical & Translational All

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Background Hereditary angioedema (HAE) is a rare disease with heterogeneous clinical symptoms. It is vitally important to predict whether an HAE patient will develop severe symptoms in clinical practice, but there are currently no predictive biomarkers for HAE stratification. Plasma N‐glycomes are disease‐specific and have great potential for the discovery of non‐invasive biomarkers. In this study, we profiled the plasma N‐glycome of HAE patients from two independent cohorts to identify candidate biomarkers. Methods Linkage‐specific sialylation derivatization combined with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry detection and automated data processing was employed to analyze the plasma N‐glycome of two independent type‐1 HAE cohorts. Results HAE patients had abnormal glycan complexity, galactosylation, and α2,3‐ and α2,6‐linked sialylation compared to healthy controls (HC). The classification models based on dysregulated glycan traits could successfully discriminate between HAE and HC with area under the curves (AUCs) being greater than 0.9. Some of the aberrant glycans showed response to therapy. Moreover, we identified a series of glycan traits with strong associations with the occurrence of laryngeal or gastrointestinal angioedema or disease severity score. Predictive models based on these traits could be used to predict disease severity (AUC > 0.9). These results were replicated in an independent cohort. Conclusions We reported the full plasma N‐glycomic signature of HAE for the first time, and identified potential biomarkers. These findings may play a critical role in predicting disease severity and guide the treatment of HAE in clinical practice. Further protein‐specific and prospective studies are needed to validate our findings.

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Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes

Cited by 88 publications

References 23 publications

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

N‐glycome signatures in human plasma: associations with physiology and major diseases

Validation of diagnostic and predictive biomarkers for hereditary angioedema via plasma N‐glycomics

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