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

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. Graphical abstract.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:65

Enthalten in:

Diabetologia - 65(2022), 7 vom: 30. Apr., Seite 1179-1184

Sprache:

Englisch

Beteiligte Personen:

Wyatt, Rebecca C. [VerfasserIn]
Hagopian, William A. [VerfasserIn]
Roep, Bart O. [VerfasserIn]
Patel, Kashyap A. [VerfasserIn]
Resnick, Brittany [VerfasserIn]
Dobbs, Rebecca [VerfasserIn]
Hudson, Michelle [VerfasserIn]
De Franco, Elisa [VerfasserIn]
Ellard, Sian [VerfasserIn]
Flanagan, Sarah E. [VerfasserIn]
Hattersley, Andrew T. [VerfasserIn]
Oram, Richard A. [VerfasserIn]
Johnson, Matthew B. [VerfasserIn]

Links:

Volltext [kostenfrei]

Themen:

ER stress
HLA
Islet autoantibodies
Monogenic
Neonatal diabetes

RVK:

RVK Klassifikation

Anmerkungen:

© The Author(s) 2022

doi:

10.1007/s00125-022-05697-3

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2130810047

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