The multiple origins of Type 1 diabetes

Diabet Med. 2013 Feb;30(2):135-46. doi: 10.1111/dme.12081.


It is widely accepted that Type 1 diabetes is a complex disease. Genetic predisposition and environmental factors favour the triggering of autoimmune responses against pancreatic β-cells, eventually leading to β-cell destruction. Over 40 susceptibility loci have been identified, many now mapped to known genes, largely supporting a dominant role for an immune-mediated pathogenesis. This role is also supported by the identification of several islet autoantigens and antigen-specific responses in patients with recent onset diabetes and subjects with pre-diabetes. Increasing evidence suggests certain viruses as a common environmental factor, together with diet and the gut microbiome. Inflammation and insulin resistance are emerging as additional cofactors, which might be interrelated with environmental factors. The heterogeneity of disease progression and clinical manifestations is likely a reflection of this multifactorial pathogenesis. So far, clinical trials have been mostly ineffective in delaying progression to overt diabetes in relatives at increased risk, or in reducing further loss of insulin secretion in patients with new-onset diabetes. This limited success may reflect, in part, our incomplete understanding of key pathogenic mechanisms, the lack of truly robust biomarkers of both disease activity and β-cell destruction, and the inability to assess the relative contributions of various pathogenic mechanisms at various time points during the course of the natural history of Type 1 diabetes. Emerging data and a re-evaluation of histopathological, immunological and metabolic findings suggest the hypothesis that unknown mechanisms of β-cell dysfunction may be present at diagnosis, and may contribute to the development of hyperglycaemia and clinical symptoms.

Publication types

  • Review

MeSH terms

  • Autoantigens / metabolism
  • Autoimmunity*
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diet / adverse effects
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hyperglycemia / etiology*
  • Hyperglycemia / genetics
  • Hyperglycemia / immunology
  • Insulin-Secreting Cells / immunology*
  • Intestines / microbiology
  • Male
  • Metagenome
  • Prediabetic State / etiology*
  • Prediabetic State / genetics
  • Prediabetic State / immunology
  • Risk Factors


  • Autoantigens