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

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.

Epigenetics in Human Obesity and Type 2 Diabetes

“…Notably, there is a growing body of literature showing that HDACs regulate glucose homeostasis and islet function (Lenoir et al., 2011, Lundh et al., 2015, Mihaylova et al., 2011, Rönn et al., 2013). An HDACi, MC1568, was recently found to improve insulin secretion in pancreatic islets from human donors with T2D (Daneshpajooh et al., 2018). MC1568 inhibits HDAC7, which has increased expression and decreased DNA methylation in pancreatic islets from diabetic versus non-diabetic donors (Daneshpajooh et al., 2017).…”

Nutritional Factors, DNA Methylation, and Risk of Type 2 Diabetes and Obesity: Perspectives and Challenges

“…There is mounting evidence showing that HDACs regulate glucose homeostasis and islet function [94]. For instance, MC1568, an HDACi, improves insulin secretion in pancreatic islets from human donors with T2D [95]. MC1568 inhibits HDAC7, the overexpression of which in clonal ß cells and rat islets results in impaired glucose-stimulated insulin secretion and mitochondrial dysfunction [96].…”

Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes

“…Several studies have investigated whether inhibitors of epigenetic enzymes may affect insulin secretion and action. Studies from our group and Thomas Mandrup‐Poulsen’s group have used inhibitors of histone deacetylases (HDACs) and lysine demethylases and studied their impact on islet function [[77‐84]. These studies support a protective β‐cell function and show improved insulin secretion when cells are exposed to these inhibitors.…”

“…These studies support a protective β‐cell function and show improved insulin secretion when cells are exposed to these inhibitors. Interestingly, treating human islets from T2D donors with a HDAC inhibitor improved insulin secretion [78]. These results should be followed up.…”