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Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes

Lernmark, Åke LU orcid ; Akolkar, Beena ; Hagopian, William ; Krischer, Jeffrey ; McIndoe, Richard ; Rewers, Marian ; Toppari, Jorma ; Vehik, Kendra LU and Ziegler, Anette-G (2023) In Journal of Internal Medicine 294(2). p.145-158
Abstract

The etiology of type 1 diabetes foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of type 1 diabetes. 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 US) observational study, children were identified at birth for the type 1 diabetes high risk HLA haplogenotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8 and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland,... (More)

The etiology of type 1 diabetes foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of type 1 diabetes. 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 US) observational study, children were identified at birth for the type 1 diabetes high risk HLA haplogenotypes 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 type 1 diabetes (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 aetiology of autoimmune type 1 diabetes. This article is protected by copyright. All rights reserved.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Internal Medicine
volume
294
issue
2
pages
145 - 158
publisher
Wiley-Blackwell
external identifiers
  • scopus:85159167827
  • pmid:37143363
ISSN
1365-2796
DOI
10.1111/joim.13648
language
English
LU publication?
yes
additional info
This article is protected by copyright. All rights reserved.
id
4e5d15d2-8aca-4b96-957e-402a48d0539f
date added to LUP
2023-05-10 22:59:10
date last changed
2024-06-02 04:49:36
@article{4e5d15d2-8aca-4b96-957e-402a48d0539f,
  abstract     = {{<p>The etiology of type 1 diabetes foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of type 1 diabetes. 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 US) observational study, children were identified at birth for the type 1 diabetes high risk HLA haplogenotypes 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 type 1 diabetes (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 aetiology of autoimmune type 1 diabetes. This article is protected by copyright. All rights reserved.</p>}},
  author       = {{Lernmark, Åke and Akolkar, Beena and Hagopian, William and Krischer, Jeffrey and McIndoe, Richard and Rewers, Marian and Toppari, Jorma and Vehik, Kendra and Ziegler, Anette-G}},
  issn         = {{1365-2796}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{2}},
  pages        = {{145--158}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Internal Medicine}},
  title        = {{Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes}},
  url          = {{http://dx.doi.org/10.1111/joim.13648}},
  doi          = {{10.1111/joim.13648}},
  volume       = {{294}},
  year         = {{2023}},
}