title: High glucose disrupts oligosaccharide recognition function via competitive inhibition: a potential mechanism for immune dysregulation in diabetes mellitus.
abstract: Diabetic complications include infection and cardiovascular disease. Within the immune system, host-pathogen and regulatory host-host interactions operate through binding of oligosaccharides by C-type lectin. A number of C-type lectins recognise oligosaccharides rich in mannose and fucose - sugars with similar structures to glucose. This raises the possibility that high glucose conditions in diabetes affect protein-oligosaccharide interactions via competitive inhibition. Mannose-binding lectin, soluble DC-SIGN and DC-SIGNR, and surfactant protein D, were tested for carbohydrate binding in the presence of glucose concentrations typical of diabetes, via surface plasmon resonance and affinity chromatography. Complement activation assays were performed in high glucose. DC-SIGN and DC-SIGNR expression in adipose tissues was examined via immunohistochemistry. High glucose inhibited C-type lectin binding to high-mannose glycoprotein and binding of DC-SIGN to fucosylated ligand (blood group B) was abrogated in high glucose. Complement activation via the lectin pathway was inhibited in high glucose and also in high trehalose - a nonreducing sugar with glucoside stereochemistry. DC-SIGN staining was seen on cells with DC morphology within omental and subcutaneous adipose tissues. We conclude that high glucose disrupts C-type lectin function, potentially illuminating new perspectives on susceptibility to infectious and inflammatory disease in diabetes. Mechanisms involve competitive inhibition of carbohydrate binding within sets of defined proteins, in contrast to broadly indiscriminate, irreversible glycation of proteins.
authors.affiliation: Clinical Sciences Research Institute, University of Warwick, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ilyas
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Soilleux
authors.forename: Paul
authors.initials: P
authors.lastname: Townsend
authors.forename: Daniel
authors.initials: D
authors.lastname: Zehnder
authors.forename: Bee K
authors.initials: BK
authors.lastname: Tan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sim
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.forename: Harpal S
authors.initials: HS
authors.lastname: Randeva
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mitchell
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D001424:Bacterial Infections; D001667:Binding, Competitive / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D037582:Complement Pathway, Mannose-Binding Lectin; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048909:Diabetes Complications; D005947:Glucose / Q000737:chemistry / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D056747:Immunomodulation; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D037601:Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D025942:Oligosaccharides, Branched-Chain / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D020349:Surface Plasmon Resonance; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D005947:Glucose; D037181:Lectins, C-Type; D037601:Mannose-Binding Lectin; D025942:Oligosaccharides, Branched-Chain; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human