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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
- Axelsson, AS;
- Mahdi, T;
- Nenonen, HA;
- Singh, T;
- Hänzelmann, S;
- Wendt, A;
- Bagge, A;
- Reinbothe, TM;
- Millstein, J;
- Yang, X;
- Zhang, B;
- Gusmao, EG;
- Shu, L;
- Szabat, M;
- Tang, Y;
- Wang, J;
- Salö, S;
- Eliasson, L;
- Artner, I;
- Fex, M;
- Johnson, JD;
- Wollheim, CB;
- Derry, JMJ;
- Mecham, B;
- Spégel, P;
- Mulder, H;
- Costa, IG;
- Zhang, E;
- Rosengren, AH
- et al.
Abstract
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.
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