Viktoria Dotz1, Roosmarijn F H Lemmers2, Karli R Reiding3, Agnes L Hipgrave Ederveen4, Aloysius G Lieverse5, Monique T Mulder6, Eric J G Sijbrands7, Manfred Wuhrer8, Mandy van Hoek9. 1. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: v.dotz@lumc.nl. 2. Department of Internal Medicine, ErasmusMC, University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Máxima Medical Center, Eindhoven, the Netherlands. Electronic address: r.lemmers@erasmusmc.nl. 3. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: k.r.reiding@lumc.nl. 4. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: a.l.hipgrave_ederveen@lumc.nl. 5. Department of Internal Medicine, Máxima Medical Center, Eindhoven, the Netherlands. Electronic address: l.lieverse@mmc.nl. 6. Department of Internal Medicine, ErasmusMC, University Medical Center, Rotterdam, the Netherlands. Electronic address: m.t.mulder@erasmusmc.nl. 7. Department of Internal Medicine, ErasmusMC, University Medical Center, Rotterdam, the Netherlands. Electronic address: e.sijbrands@erasmusmc.nl. 8. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: m.wuhrer@lumc.nl. 9. Department of Internal Medicine, ErasmusMC, University Medical Center, Rotterdam, the Netherlands. Electronic address: m.vanhoek@erasmusmc.nl.
Abstract
BACKGROUND: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes. METHODS: Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls. RESULTS: Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11). CONCLUSIONS: While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3-linked sialylation in type 2 diabetes patients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes. GENERAL SIGNIFICANCE: This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease.
BACKGROUND: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes. METHODS: Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls. RESULTS: Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11). CONCLUSIONS: While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3-linked sialylation in type 2 diabetespatients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes. GENERAL SIGNIFICANCE: This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease.
Authors: Sunny S Singh; Annemieke Naber; Viktoria Dotz; Emma Schoep; Elham Memarian; Roderick C Slieker; Petra J M Elders; Gerda Vreeker; Simone Nicolardi; Manfred Wuhrer; Eric J G Sijbrands; Aloysius G Lieverse; Leen M 't Hart; Mandy van Hoek Journal: BMJ Open Diabetes Res Care Date: 2020-07
Authors: Tyler Kim; Yixuan Xie; Qiongyu Li; Virginia M Artegoitia; Carlito B Lebrilla; Nancy L Keim; Sean H Adams; Sridevi Krishnan Journal: Eur J Nutr Date: 2021-03-26 Impact factor: 5.614
Authors: Elham Memarian; Leen M 't Hart; Mandy van Hoek; Viktoria Dotz; Roderick C Slieker; Roosmarijn F L Lemmers; Amber A van der Heijden; Femke Rutters; Giel Nijpels; Emma Schoep; Aloysius G Lieverse; Eric J G Sijbrands; Manfred Wuhrer Journal: BMJ Open Diabetes Res Care Date: 2021-10