Glycotoxin and Autoantibodies Are Additive Environmentally Determined Predictors of Type 1 Diabetes
A Twin and Population Study
- Huriya Beyan1,
- Harriette Riese2,3,
- Mohammed I. Hawa1,
- Guisi Beretta1,
- Howard W. Davidson4,
- John C. Hutton4,
- Huibert Burger3,5,
- Michael Schlosser6,7,
- Harold Snieder2,
- Bernhard O. Boehm7 and
- R. David Leslie1⇓
- 1Centre for Diabetes and Metabolic Medicine, Blizard Institute, Queen Mary, University of London, London, U.K.
- 2Unit of Genetic Epidemiology & Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- 3Interdisciplinary Center for Psychiatric Epidemiology, Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- 4Barbara Davis Center, University of Colorado Denver, Aurora, Colorado
- 5Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- 6Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany
- 7Division of Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany
- Corresponding author: R. David Leslie, .
H.Be., H.R., M.I.H., B.O.B., and R.D.L. contributed equally to this study.
In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum Nε-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.
- Received July 12, 2011.
- Accepted January 20, 2012.
- © 2012 by the American Diabetes Association.
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