Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes

Wen Bin Chen, Ling Gao, Jie Wang, Yan Gang Wang, Zheng Dong, Jiajun Zhao, Qing Sheng Mi, Li Zhou

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple lowdose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 knockout and wild type littermate controls. Mice with β-cell-specific HDAC3 deletion displayed decreased pancreatic insulin content, disrupted glucosestimulated insulin secretion, with intermittent spontaneous diabetes and dramatically enhanced susceptibility to STZ-induced diabetes. Furthermore, islet β-cell line, MIN6 cells with siRNA-mediated HDAC3 silence, showed decreased insulin gene transcription, which was mediated, at least partially, through the upregulation of suppressors of cytokine signaling 3 (SOCS3). These results indicate the critical role of HDAC3 in normal β-cell differentiation, maintenance and function.

Original languageEnglish (US)
Pages (from-to)57485-57497
Number of pages13
JournalOncotarget
Volume7
Issue number36
DOIs
StatePublished - Jan 1 2016

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Glucose Intolerance
Experimental Diabetes Mellitus
Islets of Langerhans
Histone Deacetylases
Insulin
Cell Differentiation
Maintenance
Histones
Small Interfering RNA
Chromatin
Up-Regulation
Pharmacology
Cytokines
Gene Expression
Glucose
Cell Line
Incidence
Enzymes
Genes
Proteins

Keywords

  • Autoimmune diabetes
  • Glucose tolerance
  • HDAC3
  • Insulin
  • Knockout
  • Pathology Section

ASJC Scopus subject areas

  • Oncology

Cite this

Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. / Chen, Wen Bin; Gao, Ling; Wang, Jie; Wang, Yan Gang; Dong, Zheng; Zhao, Jiajun; Mi, Qing Sheng; Zhou, Li.

In: Oncotarget, Vol. 7, No. 36, 01.01.2016, p. 57485-57497.

Research output: Contribution to journalArticle

Chen, Wen Bin ; Gao, Ling ; Wang, Jie ; Wang, Yan Gang ; Dong, Zheng ; Zhao, Jiajun ; Mi, Qing Sheng ; Zhou, Li. / Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. In: Oncotarget. 2016 ; Vol. 7, No. 36. pp. 57485-57497.
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