Title

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

Document Type

Article

Publication Date

9-6-2016

Publication Title

Oncotarget

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 low-dose 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 glucose-stimulated 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.

Medical Subject Headings

Animals; Cell Line; Diabetes Mellitus, Experimental; Female; Gene Deletion; Glucose Intolerance; Glucose Tolerance Test; Histone Deacetylases; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Knockout; Microscopy, Fluorescence; Pancreas; RNA Interference; RNA, Small Interfering; Streptozocin

PubMed ID

27542279

Volume

7

Issue

36

First Page

57485

Last Page

57497

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