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‐
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.
Discussion
Our study demonstrates that a selective class II HDAC inhibitor, MC1568, improves insulin secretion in human islets from donors with T2D. It also rescued mitochondrial dysfunction and apoptosis in clonal β-cells overexpressing Hdac7. These findings support specific HDAC7 inhibitors as a potential therapeutic option for T2D.
We recently found increased
HDAC7 expression in islets from donors with T2D and
HDAC7 expression correlated negatively with GSIS. These data suggested that HDAC7 may impair insulin secretion [
10]. Indeed, Hdac7 overexpression impaired insulin secretion in both rat islets and clonal β-cells, and resulted in increased expression of
Tcf7l2 and decreased expression of gene sets regulating DNA replication and repair as well as nucleotide metabolism in β-cells. Moreover, the impaired insulin secretion mediated by Hdac7 overexpression was restored by MC1568 treatment [
10]. To translate these findings to humans, we tested if MC1568 could improve insulin secretion in islets from human donors with T2D. Indeed, MC1568 increased GSIS in T2D islets, but had no effect on islets from non-diabetic donors. We very rarely receive islets from donors with T2D, and these unique data have been collected over a long time. However, islets from a larger number of donors should be investigated in the future to further strengthen this notion. In addition, due to the limited access to islets from donors with T2D, we could not investigate the cellular effects contributing to this improvement in insulin secretion by MC1568. Instead, to dissect the cellular mechanisms by which Hdac7 inhibition rescues the insulin secretion impairment, we treated Hdac7 overexpressing β-cells with MC1568. We found that HDAC inhibition improved the mitochondrial oxygen consumption rate and cellular ATP levels at high glucose levels in Hdac7-overexpressing cells, which support an improved mitochondrial function. These data are in line with a previous study reporting that HDAC inhibition improves oxidative metabolism and mitochondrial function in muscle cells and adipocytes [
11]. In addition, a previous study found changes in histone acetylation when oocytes were exposed to MC1568 for several relatively short time points, supporting that short exposures to MC1568 can alter the acetylation of histones [
12].
Hdac7 overexpression, i.e., mimicking the T2D situation, in clonal β-cells also resulted in increased cell death. Studies indicate that T2D is associated with β-cell loss due to various mechanisms, at least in advanced stages of the disease [
13], and increased HDAC7 may be a contributing factor in this. Our data suggest that MC1568 can prevent β-cell death induced by Hdac7 overexpression and, thus, rescue β-cell numbers. Interestingly, and in agreement with our finding, treatment with MC1568 in pancreatic explants from mice increased the pool of β- and δ-cells [
8].
In summary, 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.
Compliance with ethical standards
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