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Elevated cathepsin S serum levels in new-onset type 1 diabetes and autoantibody-positive siblings

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posted on 2024-05-03, 19:21 authored by Caroline Frørup, Mathias Høj Jensen, Martin Haupt-Jorgensen, Karsten Buschard, Joachim Størling, Flemming Pociot, Tina Fløyel

Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study’s objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and β cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-βH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-βH5 cells demonstrated induction and secretion of CTSS after exposure to pro-inflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the β cells in donors with type 1 diabetes as compared to non-diabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.

Funding

This work was funded by grants to T.F. from JDRF International (JDRF), New York, NY [3-PDF-2020-938-A-N], and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat, Denmark, and to F.P. from the Independent Research Fund Denmark [DFF-0134-00267 and DFF-4183-00031].

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