Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
(2017) In Nature Communications 8. p.15652-15652- 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... (More)
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.
(Less)
- author
- Axelsson, Annika
LU
; Mahdi, T
LU
; Nenonen, H A
LU
; Singh, Tania
LU
; Hänzelmann, S
LU
; Wendt, A
LU
; Bagge, Annika
LU
; Reinbothe, T M
LU
; Millstein, J
; Yang, X
LU
; Zhang, B.
; Gusmao, E G
; Shu, L
; Szabat, M
; Tang, Y
LU
; Wang, Jinling
LU
; Salö, Sofia
; Eliasson, L
LU
; Artner, I
LU
; Fex, M
LU
; Johnson, J D
LU
; Wollheim, C B
LU
; Derry, J M J
; Mecham, B
; Spégel, P
LU
; Mulder, H
LU
; Costa, Ivan G
; Zhang, E
LU
and Rosengren, A H
LU
(Less) - organization
-
- Diabetes - Islet Patophysiology (research group)
- Stem Cell Center
- Diabetes - Islet Cell Exocytosis (research group)
- Diabetes - Molecular Metabolism (research group)
- Celiac Disease and Diabetes Unit (research group)
- Translational Muscle Research (research group)
- Centre for Analysis and Synthesis
- Biochemistry and Structural Biology
- EXODIAB: Excellence of Diabetes Research in Sweden
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- publishing date
- 2017-06-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Journal Article
- in
- Nature Communications
- volume
- 8
- pages
- 15652 - 15652
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:28585545
- scopus:85020265594
- ISSN
- 2041-1723
- DOI
- 10.1038/ncomms15652
- language
- English
- LU publication?
- yes
- id
- 2d025ae1-70f7-4e53-80c9-06520c23440e
- date added to LUP
- 2017-06-13 12:47:15
- date last changed
- 2024-02-29 16:32:12
@article{2d025ae1-70f7-4e53-80c9-06520c23440e,
abstract = {{<p>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.</p>}},
author = {{Axelsson, Annika and Mahdi, T and Nenonen, H A and Singh, Tania and Hänzelmann, S and Wendt, A and Bagge, Annika and Reinbothe, T M and Millstein, J and Yang, X and Zhang, B. and Gusmao, E G and Shu, L and Szabat, M and Tang, Y and Wang, Jinling and Salö, Sofia and Eliasson, L and Artner, I and Fex, M and Johnson, J D and Wollheim, C B and Derry, J M J and Mecham, B and Spégel, P and Mulder, H and Costa, Ivan G and Zhang, E and Rosengren, A H}},
issn = {{2041-1723}},
keywords = {{Journal Article}},
language = {{eng}},
month = {{06}},
pages = {{15652--15652}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes}},
url = {{http://dx.doi.org/10.1038/ncomms15652}},
doi = {{10.1038/ncomms15652}},
volume = {{8}},
year = {{2017}},
}