title: Glycotoxin and autoantibodies are additive environmentally determined predictors of type 1 diabetes: a twin and population study.
abstract: In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum N(ε)-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA(+) and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA(+) and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA(+) children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target.
authors.affiliation: Centre for Diabetes and Metabolic Medicine, Blizard Institute, Queen Mary, University of London, London, UK.
authors.forename: Huriya
authors.initials: H
authors.lastname: Beyan
authors.forename: Harriette
authors.initials: H
authors.lastname: Riese
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Hawa
authors.forename: Guisi
authors.initials: G
authors.lastname: Beretta
authors.forename: Howard W
authors.initials: HW
authors.lastname: Davidson
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.forename: Huibert
authors.initials: H
authors.lastname: Burger
authors.forename: Michael
authors.initials: M
authors.lastname: Schlosser
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: R David
authors.initials: RD
authors.lastname: Leslie
mesh_terms: D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000209:etiology* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D011159:Population Surveillance; D015531:Radioimmunoprecipitation Assay; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D017127:Glycation End Products, Advanced; C024211:islet cell antibody; C048496:N(6)-carboxymethyllysine; D008239:Lysine