SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients.

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 β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual β-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 β-cells, suggesting an antiapoptotic 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 nuclear factor-κB (NF-κB) subunit p65, lower nitric oxide production, and diminished 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 NF-κB-inducible nitric oxide synthase-endoplasmic reticulum stress pathway.

• Authors: Tina Fløyel, Kira Meyerovich, Michala C Prause, Simranjeet Kaur, Caroline Frørup, Henrik B Mortensen, Lotte B Nielsen, Flemming Pociot, Alessandra K Cardozo, Joachim Størling
• Journal: Diabetes (Diabetes) Vol. 70 Issue 2 Pg. 464-476 (02 2021) ISSN: 1939-327X [Electronic] United States
• PMID: 33203694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Intracellular Signaling Peptides and Proteins
• src kinase associated phosphoprotein 2

Topics

• Adolescent
• Animals
• Apoptosis (genetics)
• Blood Glucose (genetics, metabolism)
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (diagnosis, genetics, metabolism)
• Female
• Gene Knockdown Techniques
• Genotype
• Glycemic Control
• Humans
• Insulin-Secreting Cells (metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Islets of Langerhans (metabolism)
• Male
• Polymorphism, Single Nucleotide
• Rats