Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul;65(7):1179-1184.
doi: 10.1007/s00125-022-05697-3. Epub 2022 Apr 30.

Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes

Rebecca C Wyatt  1 , William A Hagopian  2 , Bart O Roep  3 , Kashyap A Patel  1 , Brittany Resnick  4 , Rebecca Dobbs  4 , Michelle Hudson  4 ; EXE-T1D Consortium; Elisa De Franco  1 , Sian Ellard  1 , Sarah E Flanagan  1 , Andrew T Hattersley  1 , Richard A Oram  1 , Matthew B Johnson  5
Affiliations

Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes

Rebecca C Wyatt et al. Diabetologia. 2022 Jul.

Abstract

Aims/hypothesis: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM).

Methods: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39-2.9 months]; median age collected 4.6 months [IQR 1.8-27.6 months]; median diabetes duration 2 months [IQR 0.6-23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0-48.6 months]) for autoantibodies.

Results: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all).

Conclusions/interpretation: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells.

Keywords: ER stress; HLA; Islet autoantibodies; Monogenic; Neonatal diabetes.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Proportion of individuals positive for islet autoantibodies in those with a congenital monogenic beta cell defect leading to ER stress (n=75), impacting beta cell development (n=7), function (n=110) or other (n=50) and in diabetes-free control participants (n=69) (a). Proportion of individuals with a congenital monogenic beta cell defect positive for islet autoantibodies in those with (n=82) or without (n=146) an HLA risk allele (b). Antibody positive individuals (n=13) were defined as exceeding the 99th centile of index scores in 200 healthy control participants for GADA, IA-2A and/or ZnT8A. Ab neg, antibody negative; Ab pos, antibody positive
See this image and copyright information in PMC

References

    1. Bottazzo GF. Death of a Beta-cell - homicide or suicide? Diabetic Med. 1986;3(2):119–130. doi: 10.1111/j.1464-5491.1986.tb00722.x. - DOI - PubMed
    1. Roep BO, Thomaidou S, van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?) Nat Rev Endocrinol. 2021;17(3):150–161. doi: 10.1038/s41574-020-00443-4. - DOI - PMC - PubMed
    1. Marroqui L, Dos Santos RS, de Beeck AO, et al. Interferon-alpha mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes. Diabetologia. 2017;60(4):656–667. doi: 10.1007/s00125-016-4201-3. - DOI - PubMed
    1. Eizirik DL, Sammeth M, Bouckenooghe T, et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 2012;8(3):17. doi: 10.1371/journal.pgen.1002552. - DOI - PMC - PubMed
    1. Kracht MJL, van Lummel M, Nikolic T, et al. Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med. 2017;23(4):501. doi: 10.1038/nm.4289. - DOI - PubMed

Publication types