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

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Daneshpajooh, MahboubehLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups (author)

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

Article/chapterEnglish2017

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2016-10-29
Springer Science and Business Media LLC,2017

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LIBRIS-ID:oai:lup.lub.lu.se:8b162d3a-1fbc-4f5f-ae0a-25fd311aa721
https://lup.lub.lu.se/record/8b162d3a-1fbc-4f5f-ae0a-25fd311aa721URI
https://doi.org/10.1007/s00125-016-4113-2DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype
Subject category:ref swepub-contenttype

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Aims/hypothesis: Pancreatic 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). Methods: To 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. Results: Using 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/interpretation: 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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
Apoptosis
Beta cells
Epigenetic modification
HDAC7
Human pancreatic islets
Insulin secretion
MC1568
Trichostatin A
Type 2 diabetes

Added entries (persons, corporate bodies, meetings, titles ...)

Bacos, KarlLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)medk-kb0 (author)
Bysani, MadhusudhanLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)med-mur (author)
Bagge, AnnikaLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Diabetes - molekylär metabolism,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Diabetes - Molecular Metabolism(Swepub:lu)med-aib (author)
Ottosson Laakso, EmiliaLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Translationell muskelforskning,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Translational Muscle Research(Swepub:lu)med-eo_ (author)
Vikman, PetterLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Translationell muskelforskning,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Translational Muscle Research(Swepub:lu)wbl-pwi (author)
Eliasson, LenaLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups(Swepub:lu)mphy-lel (author)
Mulder, HindrikLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Diabetes - molekylär metabolism,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Diabetes - Molecular Metabolism(Swepub:lu)medk-hmu (author)
Ling, CharlotteLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)endo-cl0 (author)
Diabetes - epigenetikForskargrupper vid Lunds universitet (creator_code:org_t)

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In:Diabetologia: Springer Science and Business Media LLC60:1, s. 116-1250012-186X1432-0428

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