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J Biol Chem. 2017 Oct 27;292(43):17598-17608. doi: 10.1074/jbc.M117.804328. Epub 2017 Aug 31.

Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

Author information

1
From the Department of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts 02215.
2
Stanley Center for Psychiatric Research and.
3
Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142.
4
Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, bwagner@broadinstitute.org.
5
From the Department of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, Rohit.Kulkarni@joslin.harvard.edu.
6
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, and.
7
Harvard Stem Cell Institute, Boston Massachusetts 02215.

Abstract

Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of β-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.

KEYWORDS:

apoptosis; beta-cell (B-cell); inflammation; small molecule; type 1 diabetes

PMID:
28860191
PMCID:
PMC5663865
DOI:
10.1074/jbc.M117.804328
[Indexed for MEDLINE]
Free PMC Article

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