Glycotoxin and Autoantibodies Are Additive Environmentally Determined Predictors of Type 1 Diabetes

A Twin and Population Study

  1. R. David Leslie1
  1. 1Centre for Diabetes and Metabolic Medicine, Blizard Institute, Queen Mary, University of London, London, U.K.
  2. 2Unit of Genetic Epidemiology & Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  3. 3Interdisciplinary Center for Psychiatric Epidemiology, Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  4. 4Barbara Davis Center, University of Colorado Denver, Aurora, Colorado
  5. 5Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  6. 6Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany
  7. 7Division of Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany
  1. Corresponding author: R. David Leslie, r.d.g.leslie{at}qmul.ac.uk.
  1. H. Beyan, H.R., M.I.H., B.O.B., and R.D.L. contributed equally to this study.

Abstract

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.

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