1. Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
- Author
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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, and Rosengren, AH
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Obesity ,Diabetes ,Genetics ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Animals ,Calcium ,Calcium Channels ,Chromatin ,Diabetes Mellitus ,Experimental ,Diabetes Mellitus ,Type 2 ,Exocytosis ,Female ,Gene Expression Regulation ,Humans ,Insulin ,Insulin-Secreting Cells ,Islets of Langerhans ,Male ,Mice ,Mice ,Inbred C57BL ,Oligonucleotide Array Sequence Analysis ,Phenotype ,Phlorhizin ,RNA ,Small Interfering ,Rats ,SOXD Transcription Factors ,Valproic Acid - 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.
- Published
- 2017