title: Glycosylation failure extends to glycoproteins in gestational diabetes mellitus: evidence from reduced α2-6 sialylation and impaired immunomodulatory activities of pregnancy-related glycodelin-A.
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.
  
  
  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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong, China.
authors.forename: Cheuk-Lun
authors.initials: CL
authors.lastname: Lee
authors.forename: Philip C N
authors.initials: PC
authors.lastname: Chiu
authors.forename: Poh-Choo
authors.initials: PC
authors.lastname: Pang
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chu
authors.forename: Kai-Fai
authors.initials: KF
authors.lastname: Lee
authors.forename: Riitta
authors.initials: R
authors.lastname: Koistinen
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
authors.forename: Markku
authors.initials: M
authors.lastname: Seppälä
authors.forename: Howard R
authors.initials: HR
authors.lastname: Morris
authors.forename: Bérangère
authors.initials: B
authors.lastname: Tissot
authors.forename: Maria
authors.initials: M
authors.lastname: Panico
authors.forename: Anne
authors.initials: A
authors.lastname: Dell
authors.forename: William S B
authors.initials: WS
authors.lastname: Yeung
mesh_terms: D000328:Adult; D000653:Amniotic Fluid / Q000378:metabolism*; D000704:Analysis of Variance; D016923:Cell Death; D016640:Diabetes, Gestational / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D008401:Gas Chromatography-Mass Spectrometry; D000071816:Glycodelin; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*
chemical_list: D000071816:Glycodelin; D006023:Glycoproteins; D015850:Interleukin-6; D037102:Lectins; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D019158:N-Acetylneuraminic Acid