Abstract
AimsIt 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.MethodsHdac7 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.ResultsOverexpression 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.ConclusionsHDAC7 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.
Highlights
Both genetic and epigenetic variations contribute to impaired pancreatic islet function and type 2 diabetes (T2D) [1, 2]
MC1568 treatment reversed the negative effects of Hdac7 overexpression on β-cell number and apoptosis (Fig. 1g, h)
Our study demonstrates that a selective class II histone deacetylases (HDACs) inhibitor, MC1568, improves insulin secretion in human islets from donors with T2D
Summary
Both genetic and epigenetic variations contribute to impaired pancreatic islet function and type 2 diabetes (T2D) [1, 2]. Studies have implicated epigenetic regulators such as histone deacetylases (HDACs) in the development and function of β-cells, supporting the use of HDAC inhibitors for the treatment of diabetes. Hdac is involved in β-cell development [3], while both genetic and pharmacological inhibition of Hdac improves adult β-cell survival and function in rodents [4,5,6,7]. We reported that HDAC7 expression is upregulated in pancreatic islets from subjects with T2D and that increased Hdac levels impair insulin secretion in both isolated rodent islets and clonal β-cells. 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 Hdac and islets from donors with T2D
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
