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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 2020-11-17, 17:28 authored by Ada AdminAda Admin, Tina Fløyel, Kira Meyerovich, Michala C. Prause, Simranjeet Kaur, Caroline Frørup, Henrik B. Mortensen, Lotte B. Nielsen, Flemming Pociot, Alessandra K. Cardozo, Joachim StørlingThe 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.