Presence of immunogenic alternatively spliced insulin gene product in human pancreatic delta cells – published online 08/03/2023

René van Tienhoven, Maria J. L. Kracht, Arno R. van der Slik, Sofia Thomaidou, Anouk H. G. Wolters, Ben N. G. Giepmans, Juan Pablo Romero Riojas, Michael S. Nelson, Françoise Carlotti, Eelco J. P. de Koning, Rob C. Hoeben, Arnaud Zaldumbide, Bart O. Roep

In type 1 diabetes, insulin-producing beta cells in the pancreatic islets of Langerhans contribute to their own demise in various ways. Under stress, beta cells can generate so-called neoantigens that result from misreads from insulin mRNA (e.g. insulin defective ribosomal product [INS-DRiP]) and which strongly provoke the immune system. In this issue, van Tienhoven et al (https://doi.org/10.1007/s00125-023-05882-y) report on the surprising finding that an antibody generated against these new beta cell stress proteins selectively stains delta cells. The authors show that the target of this antibody is another insulin gene product, resulting from alternative splicing of insulin mRNA (referred to as INS-splice), that partly overlaps with INS-DRiP. Islet delta cells express this insulin gene product, INS-splice, which contains important targets of diabetes-causing T cells. The authors highlight that this finding may point to some delta cells being potential targets of autoimmunity. The authors conclude that insulin splicing may also play a role in islet development and senescence.

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