Cathepsin s is elevated in pancreatic islets and plasma in new-onset type 1 diabetes and positively associates with systemic inflammatory cytokines

Simranjeet Kaur; Demir Laila U.; Caroline Frorup; B. Madsen Jens Otto; Lars Krogvold; Gerling Ivan C.; Knut Dahl-Jorgensen; Martin Haupt-Jorgensen; Flemming Pociot; Joachim Storling; Jesper Johannesen; Tina Floyel

doi:10.1530/endoabs.110.P311

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Endocrine Abstracts (2025) 110 P311 | DOI: 10.1530/endoabs.110.P311

ECEESPE2025 Poster Presentations Diabetes and Insulin (143 abstracts)

Cathepsin s is elevated in pancreatic islets and plasma in new-onset type 1 diabetes and positively associates with systemic inflammatory cytokines

Simranjeet Kaur ¹ , Laila Ü. Demir ¹ , Caroline Frørup ¹ , 2 , Jens Otto B. Madsen ³ , Lars Krogvold ⁴ , Ivan C. Gerling ⁵ , Knut Dahl-Jørgensen ⁴ , Martin Haupt-Jorgensen ⁶ , Flemming Pociot ¹ , Joachim Størling ¹ , Jesper Johannesen ¹ , 3 & Tina Fløyel ¹ & 6

Author affiliations

¹Steno Diabetes Center Copenhagen, Clinical & Translational Research, Translational Type 1 Diabetes Research, Herlev, Denmark; ²Baker Heart and Diabetes Institute, Epigenetics in Human Health and Disease Program, Melbourne, Australia; ³Herlev and Gentofte Hospital, Department of Pediatric and Adolescent Medicine, Herlev, Denmark; ⁴Oslo University Hospital, Division of Paediatric and Adolescent Medicine, Oslo, Norway; ⁵University of Tennessee, Department of Medicine, Memphis, United States; ⁶Bartholin Institute, Rigshospitalet, Department of Pathology, Copenhagen, Denmark

JOINT1302

BackgroundAccumulating data indicate that cathepsin proteases are implicated in the development and progression of type 1 diabetes (T1D). Several cathepsins are regulated by proinflammatory cytokines in human islets/β-cells and have functions in the β-cells. We recently showed that cathepsin S (CTSS) is induced and secreted from the β-cells during T1D, and that CTSS serum levels are elevated in children with new-onset T1D and autoantibody-positive siblings.

Aims: The aims were to investigate the pancreatic islet expression of the 15 human cathepsins during T1D and to further explore the biomarker potential of CTSS in new-onset T1D.

Methods: The cathepsin gene expressions were extracted from previously generated microarray data on laser-dissected pancreatic islets from individuals with new-onset T1D (n = 5) from the Diabetes Virus Detection (DiViD) study and donors with autoantibody-positivity (AAb+, n = 12), T1D (n = 20), type 2 diabetes (T2D, n = 8), and healthy controls (n = 18) from the network of Pancreatic Organ Donors (nPOD). Cathepsin expression levels were compared between the groups using one-way ANOVA and Fisher’s LSD analyses. P-values were corrected for multiple comparisons. CTSS plasma levels were measured by ELISA at onset and 6 and 12 months after onset in a Remission cohort of children with new-onset T1D (n = 73) and analyzed for association with the inflammatory cytokines IFNγ, IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNFα, measured by MSD V-PLEX assays. A linear mixed effect model was used to evaluate changes between visits, and linear regression models were used to evaluate associations between CTSS and cytokines levels at the three time points. P < 0. 05 was considered statistically significant.

Results: Seven cathepsins were differentially expressed in islets from individuals with T1D as compared to healthy controls: CTSD, CTSH, CTSL, and CTSS in new-onset T1D, and CTSA, CTSB, and CTSZ after longer T1D duration (FDR-adjusted P < 0. 05). Only CTSS was induced in new-onset T1D. The CTSS plasma levels were decreased 12 months after onset compared to at onset (P < 0. 05) and 6 months after onset (P < 0. 01), after adjusting for age and sex. CTSS was positively associated with IFNγ (6 months, P < 0. 001), IL-10 (baseline, P < 0. 05; 12 months, P < 0. 05), and TNFα (baseline, P < 0. 05), after adjusting for age.

Conclusions: Several cathepsins are differentially expressed in the pancreatic islets during T1D. CTSS is elevated in both the islets and plasma in new-onset T1D and shows potential as an early biomarker of islet inflammation and T1D progression.