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

A Axelsson ,E Zhang ,Jinling Wang ,Tania Singh ,Claes B Wollheim ,Sofia Salö ,Le Shu ,Annika Bagge ,Hannah Nenonen ,Eduardo Gade Gusmao ,Ivan G Costa ,Bin Zhang ,James D Johnson ,Hindrik Mulder ,Brig Mecham ,Anna Wendt ,Jonathan M.j Derry ,Malin Fex ,Peter Sartipy ,Yunzhao Tang ,Lena Eliasson ,Sonja Hänzelmann ,Marta Szabat ,Taman Mahdi ,Thomas Reinbothe ,Joshua Millstein ,Xia Yang ,Isabella Artner ,Anders H Rosengren

doi:10.1038/ncomms15652

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.

Highlights

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood
We identified a set of co-expressed genes (‘module’) that is associated with T2D and reduced insulin secretion and show that human islets display expression perturbations reminiscent of b-cell dedifferentiation
We explored the possibility of using the expression profile of the 168 open chromatin genes in diabetic versus non-diabetic donors as a ‘T2D signature’ of human islets to learn more about the associated pathophysiology

Summary

Introduction

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Sox[5] 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 þ -influx and b-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key b-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. Global gene expression studies have identified a plethora of genes that are differentially expressed in islets from T2D donors compared with control subjects[7,8]. These large-scale data have not yet been maximally utilized to identify pathophysiological mechanisms. To take full advantage of such models to provide pathophysiological insights and identify new disease genes for T2D, it is important to combine bioinformatics with detailed cellular investigations, as has recently been demonstrated[10,11]

Methods

Results

Conclusion