Abstract
Aims/hypothesisPancreatic 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).MethodsTo 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.ResultsUsing 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/interpretationTaken 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.
Highlights
Data from genome-wide association studies point towards pancreatic beta cell dysfunction as a key defect causing type 2 diabetes [1]
HDAC7 expression is increased in pancreatic islets from human donors with type 2 diabetes Using RNA sequencing, we found increased HDAC7 expression in pancreatic islets from donors with type 2 diabetes compared with nondiabetic controls (Fig. 1a), confirming our previous finding [3]
We have shown that HDAC7 is upregulated in type 2 diabetic human islets, and impairs insulin secretion and mitochondrial function and induces apoptosis when overexpressed in clonal beta cells
Summary
Data from genome-wide association studies point towards pancreatic beta cell dysfunction as a key defect causing type 2 diabetes [1]. The genetic variants identified so far only explain a modest proportion of the estimated heritability of type 2 diabetes, implying that additional factors remain to be discovered [2]. Numerous enzymes, including histone deacetylases (HDACs), regulate epigenetic modifications and may thereby affect gene expression and cellular function. We recently reported decreased DNA methylation and increased gene expression of HDAC7 in pancreatic islets from human donors with type 2 diabetes [3]. We investigated the functional consequences of Hdac overexpression in beta cells and islets in an effort to dissect its potential role in diabetic islets
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