Binding of mannose-binding lectin to fructosamines: a potential link between hyperglycaemia and complement activation in diabetes

• Published in: Diabetes/metabolism research and reviews Vol. 26; no. 4; pp. 254 - 260
• Main Authors: Fortpied, Juliette, Vertommen, Didier, Van Schaftingen, Emile
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.2010; Wiley
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Chromatography, Affinity; complement; Complement Activation; diabetes; Diabetes Mellitus, Type 2 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fructosamine; Fundamental and applied biological sciences. Psychology; glycation; Humans; lectin; Lysine - analogs & derivatives; Lysine - metabolism; Mannose-Binding Lectin - blood; Mannose-Binding Lectin - metabolism; Medical sciences; Phosphotransferases (Alcohol Group Acceptor); Vertebrates: endocrinology; Endocrinopathy; Binding; Glycated protein; Mannose binding lectin; Diabetes mellitus; lectin; Activation; Complement; Glycation; Hyperglycemia; fructosamine; diabetes; Endocrinology
• ISSN: 1520-7552; 1520-7560; 1520-7560
• DOI: 10.1002/dmrr.1079

Background Complement activation via the MBL pathway has been proposed to play a role in the pathogenesis of diabetic complications. As protein glycation is increased in diabetes, we tested the possibility that the glycation product fructoselysine is a ligand for MBL and that its interaction with this protein may initiate complement activation. Methods We investigated the binding of MBL to fructoselysine by chromatography of human serum on fructoselysine‐Sepharose, followed by Western blot and mass spectrometry analysis. We also performed enzyme‐linked immunosorbent assays using purified MBL and fructoselysine‐derivatized (binding assay) or mannan‐coated plates (inhibition assay). Complement activation was determined by the fixation of C3d following incubation of fructoselysine‐derivatized plates with serum from subjects with different levels of MBL. Results MBL and its associated proteases were selectively purified from serum by chromatography on fructoselysine‐Sepharose. Competition experiments indicated that MBL had a similar affinity for mannose, fructose and fructoselysine. MBL bound, in a highly cooperative manner, to fructoselysine‐derivatized plates. This binding was associated with complement activation and was much lower with serum from subjects with low‐MBL genotypes. Conclusions MBL binding to fructoselysine and the ensuing complement activation may provide a physiopathological link between enhanced glycation and complement activation in diabetes. The cooperative character of this binding may explain the high sensitivity of diabetic complications to hyperglycaemia. Copyright © 2010 John Wiley & Sons, Ltd.