Advanced

HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells

Daneshpajooh, Mahboubeh LU ; Bacos, Karl LU ; Bysani, Madhusudhan LU ; Bagge, Annika LU ; Ottosson Laakso, Emilia LU ; Vikman, Petter LU ; Eliasson, Lena LU ; Mulder, Hindrik LU and Ling, Charlotte LU (2017) In Diabetologia 60(1). p.116-125
Abstract

Aims/hypothesis: Pancreatic beta cell dysfunction is a prerequisite for the development of type 2 diabetes. Histone deacetylases (HDACs) may affect pancreatic endocrine function and glucose homeostasis through alterations in gene regulation. Our aim was to investigate the role of HDAC7 in human and rat pancreatic islets and clonal INS-1 beta cells (INS-1 832/13). Methods: To explore the role of HDAC7 in pancreatic islets and clonal beta cells, we used RNA sequencing, mitochondrial functional analyses, microarray techniques, and HDAC inhibitors MC1568 and trichostatin A. Results: Using RNA sequencing, we found increased HDAC7 expression in human pancreatic islets from type 2 diabetic compared with non-diabetic donors. HDAC7 expression... (More)

Aims/hypothesis: Pancreatic beta cell dysfunction is a prerequisite for the development of type 2 diabetes. Histone deacetylases (HDACs) may affect pancreatic endocrine function and glucose homeostasis through alterations in gene regulation. Our aim was to investigate the role of HDAC7 in human and rat pancreatic islets and clonal INS-1 beta cells (INS-1 832/13). Methods: To explore the role of HDAC7 in pancreatic islets and clonal beta cells, we used RNA sequencing, mitochondrial functional analyses, microarray techniques, and HDAC inhibitors MC1568 and trichostatin A. Results: Using RNA sequencing, we found increased HDAC7 expression in human pancreatic islets from type 2 diabetic compared with non-diabetic donors. HDAC7 expression correlated negatively with insulin secretion in human islets. To mimic the situation in type 2 diabetic islets, we overexpressed Hdac7 in rat islets and clonal beta cells. In both, Hdac7 overexpression resulted in impaired glucose-stimulated insulin secretion. Furthermore, it reduced insulin content, mitochondrial respiration and cellular ATP levels in clonal beta cells. Overexpression of Hdac7 also led to changes in the genome-wide gene expression pattern, including increased expression of Tcf7l2 and decreased expression of gene sets regulating DNA replication and repair as well as nucleotide metabolism. In accordance, Hdac7 overexpression reduced the number of beta cells owing to enhanced apoptosis. Finally, we found that inhibiting HDAC7 activity with pharmacological inhibitors or small interfering RNA-mediated knockdown restored glucose-stimulated insulin secretion in beta cells that were overexpressing Hdac7. Conclusions/interpretation: Taken together, these results indicate that increased HDAC7 levels caused beta cell dysfunction and may thereby contribute to defects seen in type 2 diabetic islets. Our study supports HDAC7 inhibitors as a therapeutic option for the treatment of type 2 diabetes.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apoptosis, Beta cells, Epigenetic modification, HDAC7, Human pancreatic islets, Insulin secretion, MC1568, Trichostatin A, Type 2 diabetes
in
Diabetologia
volume
60
issue
1
pages
116 - 125
publisher
Springer Verlag
external identifiers
  • scopus:84992709105
  • wos:000389634000015
ISSN
0012-186X
DOI
10.1007/s00125-016-4113-2
language
English
LU publication?
yes
id
8b162d3a-1fbc-4f5f-ae0a-25fd311aa721
date added to LUP
2016-11-14 12:06:07
date last changed
2018-11-21 21:27:21
@article{8b162d3a-1fbc-4f5f-ae0a-25fd311aa721,
  abstract     = {<p>Aims/hypothesis: Pancreatic beta cell dysfunction is a prerequisite for the development of type 2 diabetes. Histone deacetylases (HDACs) may affect pancreatic endocrine function and glucose homeostasis through alterations in gene regulation. Our aim was to investigate the role of HDAC7 in human and rat pancreatic islets and clonal INS-1 beta cells (INS-1 832/13). Methods: To explore the role of HDAC7 in pancreatic islets and clonal beta cells, we used RNA sequencing, mitochondrial functional analyses, microarray techniques, and HDAC inhibitors MC1568 and trichostatin A. Results: Using RNA sequencing, we found increased HDAC7 expression in human pancreatic islets from type 2 diabetic compared with non-diabetic donors. HDAC7 expression correlated negatively with insulin secretion in human islets. To mimic the situation in type 2 diabetic islets, we overexpressed Hdac7 in rat islets and clonal beta cells. In both, Hdac7 overexpression resulted in impaired glucose-stimulated insulin secretion. Furthermore, it reduced insulin content, mitochondrial respiration and cellular ATP levels in clonal beta cells. Overexpression of Hdac7 also led to changes in the genome-wide gene expression pattern, including increased expression of Tcf7l2 and decreased expression of gene sets regulating DNA replication and repair as well as nucleotide metabolism. In accordance, Hdac7 overexpression reduced the number of beta cells owing to enhanced apoptosis. Finally, we found that inhibiting HDAC7 activity with pharmacological inhibitors or small interfering RNA-mediated knockdown restored glucose-stimulated insulin secretion in beta cells that were overexpressing Hdac7. Conclusions/interpretation: Taken together, these results indicate that increased HDAC7 levels caused beta cell dysfunction and may thereby contribute to defects seen in type 2 diabetic islets. Our study supports HDAC7 inhibitors as a therapeutic option for the treatment of type 2 diabetes.</p>},
  author       = {Daneshpajooh, Mahboubeh and Bacos, Karl and Bysani, Madhusudhan and Bagge, Annika and Ottosson Laakso, Emilia and Vikman, Petter and Eliasson, Lena and Mulder, Hindrik and Ling, Charlotte},
  issn         = {0012-186X},
  keyword      = {Apoptosis,Beta cells,Epigenetic modification,HDAC7,Human pancreatic islets,Insulin secretion,MC1568,Trichostatin A,Type 2 diabetes},
  language     = {eng},
  number       = {1},
  pages        = {116--125},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells},
  url          = {http://dx.doi.org/10.1007/s00125-016-4113-2},
  volume       = {60},
  year         = {2017},
}