Glycosylation Failure Extends to Glycoproteins in Gestational Diabetes Mellitus

Abstract

OBJECTIVEGestational 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 METHODSGdA 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.RESULTSGDM 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.CONCLUSIONSTaken together, this study provides the first direct evidence for altered enzymatic glycosylation and impaired bioactivity of GdA in GDM patients.

Human Milk Secretory Immunoglobulin A and Lactoferrin N-Glycans Are Altered in Women with Gestational Diabetes Mellitus

“…No reports to date demonstrate dysregulated glycosylation patterns of milk glycoproteins from women with GDM. Yet our results are in line with the finding of Lee et al (20), who reported reduced sialic acid, mannose residues, and impaired immunomodulatory functions of the endometrial glycoprotein, glycodelin A, isolated from amniotic fluid from women with compared with those without GDM. These data suggest that regulated glycemia is required for normal glycosyl transferase activity involving the terminal sialylation of N-linked glycoproteins.…”

“…GDM has immediate and lasting consequences in women and their infants exposed to maternal diabetes in utero (14)(15)(16). Hyperglycemia results in aberrant carbohydrate metabolism that contributes to the pathogenesis of the disease in part through increased flux through the hexosamine biosynthetic pathway (17,18) and altered activities of cellular glycosyltransferases and glycosidases (19,20). Yet, very little is known about the effect of GDM on lactation and milk components.…”

N-Glycosylation Is Critical for the Stability and Intracellular Trafficking of Glucose Transporter GLUT4

“…The results of the present study provide evidence that the N-glycan on GLUT4 not only plays a general role in protein stability, but also has a function in GLUT4 sorting and insulin responsiveness. It should be noted that several studies have demonstrated changes of N-glycan profiles under diabetic conditions (43)(44)(45)(46), and the effects of glycan profile alterations, especially in GLUT4, on the insulin resistance phenotype in type 2 diabetes should therefore be carefully investigated in future studies. Clarification of the key factors involved in N-glycan-related intracellular trafficking will be imperative for understanding the precise roles of the N-glycan functions in GLUT4.…”

Effect of Agmatine on Actin Polymerization Dynamics in Wga-Stimulated Leukocytes Under Diabetes Mellitus in Rats

“…Гіперглікемія у разі діабету викликає порушення вуглеводного обміну й утворення кінцевих продуктів глікозилювання -AGEs (з англ. advanced glycation end products), що приз водить до зміни експресії генів і активно-сті клітинних глікозилтрансфераз і глікозидаз -ензимів синтезу глікокон'югатів [7]. Останні відіграють важливу роль у різних біологічних процесах, зокрема, гомеостазі глюкози, конт-ролі якості білків, запаленні, міжклітинному сигналюванні та клітинній адгезії.…”