Glycosylation Failure Extends to Glycoproteins in Gestational Diabetes Mellitus
Open Access
- 21 February 2011
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 60 (3), 909-917
- https://doi.org/10.2337/db10-1186
Abstract
OBJECTIVE: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy. Patients with GDM are at risk for high fetal mortality and gestational complications associated with reduced immune tolerance and abnormal carbohydrate metabolism. Glycodelin-A (GdA) is an abundant decidual glycoprotein with glycosylation-dependent immunomodulatory activities. We hypothesized that aberrant carbohydrate metabolism in GDM was associated with changes in glycosylation of GdA, leading to defective immunomodulatory activities.RESEARCH DESIGN AND METHODS: GdA in the amniotic fluid from women with normal (NGdA) and GDM (DGdA) pregnancies was purified by affinity chromatography. Structural analysis of protein glycosylation was preformed by lectin-binding assay and mass spectrometry. Cytotoxicity, cell death, cytokine secretion, and GdA binding of the GdA-treated lymphocytes and natural killer (NK) cells were determined. The sialidase activity in the placental tissue from normal and GDM patients was measured.RESULTS: GDM affected the glycosylation but not the protein core of GdA. Specifically, DGdA had a lower abundance of α2-6–sialylated and high-mannose glycans and a higher abundance of glycans with Sda (NeuAcα2-3[GalNAcβ1-4]Gal) epitopes compared with NGdA. DGdA had reduced immuosuppressive activities in terms of cytotoxicity on lymphocytes, inhibitory activities on interleukin (IL)-2 secretion by lymphocytes, stimulatory activities on IL-6 secretion by NK cells, and binding to these cells. Desialylation abolished the immunomodulation and binding of NGdA. Placental sialidase activity was increased in GDM patients, which may account for the reduced sialic acid content of DGdA.CONCLUSIONS: Taken together, this study provides the first direct evidence for altered enzymatic glycosylation and impaired bioactivity of GdA in GDM patients.Keywords
This publication has 53 references indexed in Scilit:
- Effects of Differential Glycosylation of Glycodelins on Lymphocyte SurvivalJournal of Biological Chemistry, 2009
- Pregnancy and diabetes scenario around the world: ChinaInternational Journal of Gynecology & Obstetrics, 2009
- ORIGINAL ARTICLE: Glycodelin A Induces a Tolerogenic Phenotype in Monocyte-Derived Dendritic Cells In vitroAmerican Journal of Reproductive Immunology, 2008
- Carbohydrate-based experimental therapeutics for cancer, HIV/AIDS and other diseasesActa Histochemica, 2007
- T cell recognition and immunity in the fetus and motherCellular Immunology, 2007
- α2,6-Sialylation promotes binding of placental protein 14 via its Ca2+-dependent lectin activity: insights into differential effects on CD45RO and CD45RA T cellsGlycobiology, 2005
- Targeting glycosylation as a therapeutic approachNature Reviews Drug Discovery, 2002
- Gestational Diabetes MellitusNew England Journal of Medicine, 1999
- Raised Serum Sialic Acid Concentration in NIDDM Patients With and Without Diabetic NephropathyDiabetes Care, 1996
- Sialic Acid Content and Sialidase Activity of Polymorphonuclear Leucocytes in Diabetes MellitusThe American Journal of the Medical Sciences, 1984