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SKAP2, a candidate gene for type 1 diabetes, regulates β-cell apoptosis and glycaemic control in newly diagnosed patients

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posted on 17.11.2020, 17:28 by Ada Admin, Tina Fløyel, Kira Meyerovich, Michala C. Prause, Simranjeet Kaur, Caroline Frørup, Henrik B. Mortensen, Lotte B. Nielsen, Flemming Pociot, Alessandra K. Cardozo, Joachim Størling
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 β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell function during first year after diagnosis. In INS-1E cells and rat and human islets, pro-inflammatory 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 anti-apoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis which correlated with reduced nuclear content of S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NFκB-iNOS-ER stress pathway.

Funding

Work in the J.S group was funded by the Independent Research Fund Denmark (DFF-1331-00163A and DFF-7016-00282). Work in the A.K.C. group was supported by National Funds from Scientific Research (FNRS, Belgium; convention PDR T.0107.16) and the Excellence of Science grant (FNRS, Belgium, convention 30826052).

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