title: HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, 20502, Malmö, Sweden.
authors: Mahboubeh
authors: M
authors: Daneshpajooh
authors: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, 20502, Malmö, Sweden.
authors: Karl
authors: K
authors: Bacos
authors: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, 20502, Malmö, Sweden.
authors: Madhusudhan
authors: M
authors: Bysani
authors: Molecular Metabolism Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors: Annika
authors: A
authors: Bagge
authors: Diabetes and Endocrinology Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors: Emilia
authors: E
authors: Ottosson Laakso
authors: Diabetes and Endocrinology Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors: Petter
authors: P
authors: Vikman
authors: Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors: Lena
authors: L
authors: Eliasson
authors: Molecular Metabolism Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden.
authors: Hindrik
authors: H
authors: Mulder
authors: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, 20502, Malmö, Sweden. charlotte.ling@med.lu.se.
authors: Charlotte
authors: C
authors: Ling
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006442:Glycated Hemoglobin / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D006442:Glycated Hemoglobin; D006655:Histone Deacetylases; D007328:Insulin; C543273:HDAC7 protein, human
keywords: Apoptosis; Beta cells; Epigenetic modification; HDAC7; Human pancreatic islets; Insulin secretion; MC1568; Trichostatin A; Type 2 diabetes