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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes

Journal article
Authors A. S. Axelsson
T. Mahdi
H. A. Nenonen
T. Singh
S. Hänzelmann
A. Wendt
A. Bagge
T. M. Reinbothe
J. Millstein
X. Yang
B. Zhang
E. G. Gusmao
L. Shu
M. Szabat
Y. Tang
J. Wang
S. Salö
L. Eliasson
I. Artner
M. Fex
J. D. Johnson
C. B. Wollheim
J. M. J. Derry
B. Mecham
P. Spégel
H. Mulder
I. G. Costa
E. Zhang
Anders H. Rosengren
Published in Nature Communications
Volume 8
ISSN 2041-1723
Publication year 2017
Published at Institute of Neuroscience and Physiology
Language en
Links doi.org/10.1038/ncomms15652
Keywords Animalia
Subject categories Endocrinology and Diabetes

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 Ca 2+-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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