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
- 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
-
- scopus:85020265594
- pmid:28585545
- 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
- 2025-01-07 15:15:31
@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}}, }