Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients

Tina Fløyel, Kira Meyerovich, Michala C. Prause, Simranjeet Kaur, Caroline Frørup, Henrik B. Mortensen, Lotte B. Nielsen, Flemming Pociot, Alessandra K. Cardozo, Joachim Størling*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

10 Citations (Scopus)

Abstract

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the b-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual b-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced ap-optosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-kB (NF-kB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticu-lum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls b-cell sensitivity to cytokines possibly by affecting the NF-kB–inducible nitric oxide synthase– endoplasmic reticulum stress pathway.

Original languageEnglish
JournalDiabetes
Volume70
Issue number2
Pages (from-to)464-476
Number of pages13
ISSN0012-1797
DOIs
Publication statusPublished - 2021

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