Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes
- PMID: 37143363
- PMCID: PMC10524683
- DOI: 10.1111/joim.13648
Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes
Abstract
The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.
Keywords: autoantibodies; autoimmune disease; autoimmunity; immunity; type 1 diabetes mellitus; virus etiology.
© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Conflict of interest statement
Conflicts of interest: The authors declare no conflicts of interest.
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References
-
- Roep BO, Stobbe I, Duinkerken G, et al. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes 1999; 48: 484–90. - PubMed
-
- Burke GW 3rd, Vendrame F, Virdi SK, et al. Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity. Curr Diab Rep 2015; 15: 121. - PubMed
-
- Hahl J, Simell T, Ilonen J, Knip M and Simell O. Costs of predicting IDDM. Diabetologia 1998; 41: 79–85. - PubMed
-
- Ziegler AG, Hummel M, Schenker M and Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 1999; 48: 460–8. - PubMed
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