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.

Summary: Disease associations provide useful aetiological clues in relation to diseases of unknown causation; this holds particularly for auto‐immune disorders which tend to occur together in individuals and in related family members. Nine patients suffering from both multiple sclerosis and presumed auto‐immune disorder were found from a survey of case records of 326 patients with multiple sclerosis admitted to a large city hospital between 1955 and 1970. There was autoimmune disease affecting the thyroid gland in four cases, the stomach in two and the adrenal gland in one, and there were two cases of rheumatoid arthritis and one of pemphigus vulgaris. Such associations are relevant to the concept of an auto‐immune pathogenesis for multiple sclerosis, but with reservations based on the uncertain prevalence of these diseases in Australia and the ascertainment errors inherent in this type of study.