Autoimmunity plays a role in the onset of diabetes after 40 years of age

Research output: Contribution to journalArticle


Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.


  • Olov Rolandsson
  • Christiane S. Hampe
  • Stephen J. Sharp
  • Eva Ardanaz
  • Heiner Boeing
  • Guy Fagherazzi
  • Francesca Romana Mancini
  • Kim Overvad
  • Maria Dolores Chirlaque
  • Miren Dorronsoro
  • Marc J. Gunter
  • Rudolf Kaaks
  • Timothy J. Key
  • Kay Tee Khaw
  • Vittorio Krogh
  • Tilman Kühn
  • Domenico Palli
  • Salvatore Panico
  • Carlotta Sacerdote
  • Maria José Sánchez
  • Gianluca Severi
  • Annemieke M.W. Spijkerman
  • Rosario Tumino
  • Yvonne T. van der Schouw
  • Elio Riboli
  • Nita G. Forouhi
  • Claudia Langenberg
  • Nicholas J. Wareham
External organisations
  • Umeå University
  • University of Washington
  • CIBER Epidemiology and Public Health (CIBERESP)
  • Health Research Institute of Navarra (IDISNA)
  • German Institute of Human Nutrition
  • Centre for Research in Epidemiology and Population Health (CESP)
  • Skåne University Hospital
  • Aarhus University
  • Aalborg University Hospital
  • Murcia Regional Health Council
  • Public Health Division of Gipuzkoa
  • Biodonostia Health Research Institute
  • International Agency for Research on Cancer, World Health Organization
  • German Cancer Research Centre
  • University of Oxford
  • Addenbrooke's Hospital
  • Istituto Nazionale dei Tumori
  • Institute for Cancer Research, Prevention and Clinical Network (ISPRO)
  • University of Naples Federico II
  • Citta' della Salute e della Scienza Hospital-University of Turin
  • Andalusian School Of Public Health (EASP)
  • University of Granada
  • University of Paris-Sud
  • National Institute for Public Health and the Environment (RIVM)
  • Civic and M.P Arezzo Hospital
  • L’ Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.)
  • University Medical Center Utrecht
  • Imperial College London
  • University of Cambridge
  • Institute of Metabolic Science
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes


  • Autoantibody, Autoimmunity, Genetic risk score, Incident diabetes, Type 1 diabetes, Type 2 diabetes
Original languageEnglish
Pages (from-to)266-277
Number of pages12
Early online date2019 Nov
Publication statusPublished - 2020
Publication categoryResearch