HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells

Daneshpajooh, M; Bacos, Karl; Bysani, Madhusudhan; Bagge, Annika; Laakso, Emilia Ottosson; Vikman, Petter; Eliasson, Lena; Mulder, Hindrik; Ling, Charlotte

doi:10.1007/s00125-016-4113-2

Cited by 71 publications

(52 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…All experiments were performed as described [10]. Treatment with the MC1568 HDAC inhibitor was started 24 h post-transfection, and the inhibitor was removed before experiments were initiated.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Histone deacetylases (HDACs) have a broad impact on the development of human disease by regulating histone modification and gene transcription (Mathias, Guise, & Cristea, 2015;Mielcarek, Zielonka, Carnemolla, Marcinkowski, & Guidez, 2015). Class II HDAC4, 5, 7, and 9 modulate endocrine cell function and glucose homeostasis in skeletal muscles, adipose tissue, and liver (Daneshpajooh et al, 2017;Lenoir et al, 2011;Mathias et al, 2015;Mihaylova et al, 2011). In addition, HDAC4 was also found to be a key regulator controlling the pancreatic β/δ lineage during embryogenesis (Lenoir et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

HDAC4 mutations cause diabetes and induce β‐cell FoxO1 nuclear exclusion

Gong

Liang

et al. 2019

Molec Gen & Gen Med

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Background Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β‐cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis. Methods We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease‐causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic β‐cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT‐PCR to measure the β‐cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic β‐cells. Results We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of β‐cell loss. In mouse pancreatic β‐cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down‐regulate β‐cell‐specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1. Conclusion Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the β‐cell function including insulin secretion, resulting in diabetes.

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Role of Epigenetics and Metabolomics in Predicting Endothelial Dysfunction in Type 2 Diabetes

Di Pietrantonio,

Cappellacci,

Mandatori

et al. 2023

Advanced Biology

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Type 2 diabetes (T2D) is a worldwide health problem and cardiovascular disease (CVD) is a leading cause of morbidity and mortality in T2D patients, making the prevention of CVD onset a major priority. It is therefore crucial to optimize diagnosis and treatment to reduce this burden. Endothelial dysfunction is one of the most important prognostic factors for CVD progression, thus novel approaches to identify the early phase of endothelial dysfunction may lead to specific preventive measures to reduce the occurrence of CVD. Nowadays, multiomics approaches have provided unprecedented opportunities to stratify T2D patients into endotypes, improve therapeutic treatment and outcome and amend the survival prediction. Among omics strategies, epigenetics and metabolomics are gaining increasing interest. Recently, a dynamic correlation between metabolic pathways and gene expression through chromatin remodeling, such as DNA methylation, has emerged, indicating new perspectives on the regulatory networks impacting cellular processes. Thus, a better understanding of epigenetic‐metabolite relationships can provide insight into the physiological processes altered early in the endothelium that ultimately head to disease development. Here, recent studies on epigenetics and metabolomics related to CVD prevention potentially useful to identify disease biomarkers, as well as new therapies hopefully targeting the early phase of endothelial dysfunction are highlighted.

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HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells

Abstract: Taken 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.

Cited by 71 publications

References 37 publications

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

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

HDAC4 mutations cause diabetes and induce β‐cell FoxO1 nuclear exclusion

Role of Epigenetics and Metabolomics in Predicting Endothelial Dysfunction in Type 2 Diabetes

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