A PDF file should load here. If you do not see its contents
the file may be temporarily unavailable at the journal website
or you do not have a PDF plug-in installed and enabled in your browser.
Alternatively, you can download the file locally and open with any standalone PDF reader:
https://link.springer.com/content/pdf/10.1007%2Fs00592-018-1201-4.pdf
MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues β-cell dysfunction caused by Hdac7 upregulation
Acta Diabetologica
pp 1–5 | Cite as
MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues β-cell dysfunction caused by Hdac7 upregulation
AuthorsAuthors and affiliations
Mahboubeh DaneshpajoohLena EliassonKarl BacosCharlotte Ling
Open Access
Original Article
First Online: 07 August 2018
Received: 18 May 2018
Accepted: 25 July 2018
1 Shares 157 Downloads
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 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.
KeywordsType 2 diabetes Insulin secretion MC1568 Human pancreatic islets HDAC inhibitor Epigenetics
Abbreviations
FCCP
Carbonyl cyanide p-trifluoromethoxyphenylhydrazone
BR
Basal respiration
GSR
Glucose-stimulated respiration
HDAC
Histone deacetylase
mOCR
Mitochondrial oxygen consumption rate
Oligo
Oligomycin
OCR
Oxygen consumption rate
SAB
Secretion assay buffer
T2D
Type 2 diabetes
Managed by Massimo Porta.
The authors dedicate this article to the memory of Mahboubeh Daneshpajooh, who sadly passed away during the preparation of the manuscript.
Karl Bacos and Charlotte Ling have contributed equally.
Introduction
Both genetic and epigenetic variations contribute to impaired pancreatic islet function and type 2 diabetes (T2D) [1, 2]. Studies have also implicated epigenetic regulators such as histone deacetylases (HDACs) in the development and function of β-cells, thus supporting the use of HDAC inhibitors for the treatment of diabetes. For example, Hdac3 is involved in β-cell development [3], while both genetic and pharmacological inhibition of Hdac3 improves adult β-cell survival and function in rodents [4, 5, 6, 7]. In addition, knockout of Hdac5 or -9 leads to an increased pool of insulin producing β-cells [8] and the HDAC inhibitor valproic acid increases β-cell numbers and function in streptozotocin treated rats [9]. Recently, we reported that HDAC7 expression is upregulated in pancreatic islets from subjects with T2D and that increased Hdac7 levels impair insulin secretion in both isolated rodent islets and clonal β-cells. Furthermore, pharmacological and genetic inhibition of Hdac7 rescued the defects in insulin secretion [10]. The present study aimed to further explore the promise of HDAC7 as a novel therapeutic target in treatment of T2D via evaluating the effects of the HDAC inhibitor MC1568 in clonal β-cells overexpressing Hdac7 and islets from donors with T2D.
Methods
Human islets
Pancreatic islets were obtained from the Nordic Network for Islet Transplantation, Uppsala University, Sweden. Informed consent was obtained from pancreatic donors or their relatives in accordance with the approval by the local ethics committee regarding organ donation for medical research. Islets were hand-picked and randomly selected for treatment with 1 µmol/l MC1568 for 24 h after which the inhibitor was removed. Islet were then preincubated in secretion assay buffer (SAB) [10] containing 2.8 mmol/l glucose for 1 h (8–12 islets/well, 5–10 wells per condition). All islets in each well were then randomly transferred to new plates containing fresh SAB with 2.8 or 16.7 mmol/l glucose, and incubated for 1 h at 37 °C. The buffer was harvested and islets lysed for the extraction of insulin content. Insulin in buffer and lysate was measured with an ELISA (Mercodia, Sweden), and secretion was normalized to total insulin content.
Hdac7 overexpression in clonal β-cells
Hdac7 with or without a c-terminal HA-tag was overexpressed in ra (...truncated)