Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients
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Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients. / Fløyel, Tina; Meyerovich, Kira; Prause, Michala C.; Kaur, Simranjeet; Frørup, Caroline; Mortensen, Henrik B.; Nielsen, Lotte B.; Pociot, Flemming; Cardozo, Alessandra K.; Størling, Joachim.
In: Diabetes, Vol. 70, No. 2, 2021, p. 464-476.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients
AU - Fløyel, Tina
AU - Meyerovich, Kira
AU - Prause, Michala C.
AU - Kaur, Simranjeet
AU - Frørup, Caroline
AU - Mortensen, Henrik B.
AU - Nielsen, Lotte B.
AU - Pociot, Flemming
AU - Cardozo, Alessandra K.
AU - Størling, Joachim
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.2337/db20-0092
DO - 10.2337/db20-0092
M3 - Journal article
C2 - 33203694
AN - SCOPUS:85099803658
VL - 70
SP - 464
EP - 476
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 2
ER -
ID: 256628774