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MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues β-cell dysfunction caused by Hdac7 upregulation

Daneshpajooh, Mahboubeh LU ; Eliasson, Lena LU ; Bacos, Karl LU and Ling, Charlotte LU (2018) In Acta Diabetologica 55(12). p.1231-1235
Abstract

Aims: It has in recent years been established that epigenetic changes contribute to β-cell dysfunction and type 2 diabetes (T2D). For example, we have showed that the expression of histone deacetylase 7 (HDAC7) is increased in pancreatic islets of individuals with T2D and that increased levels of Hdac7 in β-cells impairs insulin secretion. The HDAC inhibitor MC1568 rescued this secretory impairment, suggesting that inhibitors specific for HDAC7 may be useful clinically in the treatment of T2D. The aim of the current study was to further explore HDAC7 as a novel therapeutic target in T2D. Methods: Hdac7 was overexpressed in clonal β-cells followed by the analysis of insulin secretion, mitochondrial function, as well as cell number and... (More)

Aims: It has in recent years been established that epigenetic changes contribute to β-cell dysfunction and type 2 diabetes (T2D). For example, we have showed that the expression of histone deacetylase 7 (HDAC7) is increased in pancreatic islets of individuals with T2D and that increased levels of Hdac7 in β-cells impairs insulin secretion. The HDAC inhibitor MC1568 rescued this secretory impairment, suggesting that inhibitors specific for HDAC7 may be useful clinically in the treatment of T2D. The aim of the current study was to further explore HDAC7 as a novel therapeutic target in T2D. Methods: Hdac7 was overexpressed in clonal β-cells followed by the analysis of insulin secretion, mitochondrial function, as well as cell number and apoptosis in the presence or absence of MC1568. Furthermore, the effect of MC1568 on insulin secretion in human pancreatic islets from non-diabetic donors and donors with T2D was also studied. Results: Overexpression of Hdac7 in clonal β-cells significantly reduced insulin secretion, mitochondrial respiration, and ATP content, while it increased apoptosis. These impairments were all rescued by treatment with MC1568. The inhibitor also increased glucose-stimulated insulin secretion in islets from donors with T2D, while having no effect on islets from non-diabetic donors. Conclusions: HDAC7 inhibition protects β-cells from mitochondrial dysfunction and apoptosis, and increases glucose-stimulated insulin secretion in islets from human T2D donors. Our study supports specific HDAC7 inhibitors as novel options in the treatment of T2D.

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Contribution to journal
publication status
published
subject
keywords
Epigenetics, HDAC inhibitor, Human pancreatic islets, Insulin secretion, MC1568, Type 2 diabetes
in
Acta Diabetologica
volume
55
issue
12
pages
1231 - 1235
publisher
Springer
external identifiers
  • scopus:85051295115
ISSN
0940-5429
DOI
10.1007/s00592-018-1201-4
language
English
LU publication?
yes
id
96fd5106-eee1-4f0b-b4d1-2a3ef813286f
date added to LUP
2018-09-12 09:27:57
date last changed
2019-05-12 04:53:23
@article{96fd5106-eee1-4f0b-b4d1-2a3ef813286f,
  abstract     = {<p>Aims: It has in recent years been established that epigenetic changes contribute to β-cell dysfunction and type 2 diabetes (T2D). For example, we have showed that the expression of histone deacetylase 7 (HDAC7) is increased in pancreatic islets of individuals with T2D and that increased levels of Hdac7 in β-cells impairs insulin secretion. The HDAC inhibitor MC1568 rescued this secretory impairment, suggesting that inhibitors specific for HDAC7 may be useful clinically in the treatment of T2D. The aim of the current study was to further explore HDAC7 as a novel therapeutic target in T2D. Methods: Hdac7 was overexpressed in clonal β-cells followed by the analysis of insulin secretion, mitochondrial function, as well as cell number and apoptosis in the presence or absence of MC1568. Furthermore, the effect of MC1568 on insulin secretion in human pancreatic islets from non-diabetic donors and donors with T2D was also studied. Results: Overexpression of Hdac7 in clonal β-cells significantly reduced insulin secretion, mitochondrial respiration, and ATP content, while it increased apoptosis. These impairments were all rescued by treatment with MC1568. The inhibitor also increased glucose-stimulated insulin secretion in islets from donors with T2D, while having no effect on islets from non-diabetic donors. Conclusions: HDAC7 inhibition protects β-cells from mitochondrial dysfunction and apoptosis, and increases glucose-stimulated insulin secretion in islets from human T2D donors. Our study supports specific HDAC7 inhibitors as novel options in the treatment of T2D.</p>},
  author       = {Daneshpajooh, Mahboubeh and Eliasson, Lena and Bacos, Karl and Ling, Charlotte},
  issn         = {0940-5429},
  keyword      = {Epigenetics,HDAC inhibitor,Human pancreatic islets,Insulin secretion,MC1568,Type 2 diabetes},
  language     = {eng},
  month        = {08},
  number       = {12},
  pages        = {1231--1235},
  publisher    = {Springer},
  series       = {Acta Diabetologica},
  title        = {MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues β-cell dysfunction caused by Hdac7 upregulation},
  url          = {http://dx.doi.org/10.1007/s00592-018-1201-4},
  volume       = {55},
  year         = {2018},
}