We report the case of a woman who underwent a partial pancreatectomy for a serous cystadenoma when aged 56 years. She had been diagnosed with diabetes 6 years before and had Hashimoto’s thyroiditis. Despite positive anti-GAD autoantibodies (GADA) and previous surgery, she was transiently weaned off long-acting insulin. Blood glucose levels remained well controlled with low-dose long-acting insulin. Insulin needs eventually increased 8 years after surgery, in conjunction with anti-zinc transporter 8 (ZnT8) seroconversion and decreasing residual C-peptide. We hypothesised that the surgical pancreas specimens and blood autoimmune T cell responses may provide correlates of this indolent clinical course.
Beta and alpha cell area and insulitis were quantified on pancreas head tissue sections obtained at surgery. Blood T cell responses against beta cell antigens were analysed by enzyme-linked immunospot.
Pancreas sections displayed reduced beta cell and normal alpha cell area (0.27% and 0.85% of section area, respectively). High-grade insulitis was observed, mostly in insulin-containing islets, with a peri-insulitis pattern enriched in T cells positive for regulatory forkhead box protein 3 (FOXP3). In vitro challenge with beta cell antigens of circulating T cells collected 4 and 9 years after surgery revealed dominant and persistent IL-10 responses; IFN-γ responses increasing at 9 years, after anti-ZnT8 seroconversion, was observed.
Despite persistent GADA and the histopathological finding of insulitis and decreased beta cell area 6 years after diabetes diagnosis, glycaemic control was maintained with low-dose insulin up to 8 years after surgery. Regulated T cell responses towards beta cell antigens and FOXP3-positive peri-insulitis suggest spontaneous long-term regulation of islet autoimmunity after substantial beta cell loss, and eventual autoimmune progression upon anti-ZnT8 seroconversion.
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Diabetes Virus Detection
Forkhead box protein 3
Islet antigen 2
Peripheral blood mononuclear cell
Effector T cell
Regulatory T cell
Zinc transporter 8
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We thank R. Scharfmann (Inserm U1016, Cochin Institute, Paris) for reviewing the manuscript.
Authors’ relationships and activities
The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
This work was performed within the Département Hospitalo-Universitaire (DHU) AutHorS and supported by grants from the JDRF (2-SRA-2016-164-Q-R), the Fondation pour la Recherche Medicale (EQU20193007831), the Agence Nationale de la Recherche (ANR-19-CE15–0014-01) and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 and 945268 (INNODIA and INNODIA HARVEST), which receive support from the EU Horizon 2020 programme, the European Federation of Pharmaceutical Industries and Associations, JDRF and The Leona M. & Harry B. Helmsley Charitable Trust. ZZ is supported by JDRF Postdoctoral Fellowship 3-PDF-2020-942-A-N. The funding sources had no involvement in study design, collection, analysis and interpretation of data, writing of the report or in the decision to submit the manuscript.
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Faucher, P., Beuvon, F., Fignani, D. et al. Immunoregulated insulitis and slow-progressing type 1 diabetes after duodenopancreatectomy. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05563-8
- Insulin secretion
- Regulatory T cells
- Type 1 diabetes