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

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.