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Anti‐diabetic effects of class 1 histone deacetylase inhibition in a rodent model of type 2 diabetes mellitus
Author(s) -
Johnson Emily,
Marsh Susan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1273.6
Subject(s) - romidepsin , histone deacetylase , endocrinology , medicine , gene knockdown , histone deacetylase inhibitor , insulin , apoptosis , biology , histone , biochemistry , gene
Histone deacetylases (HDACs) have diverse roles in non‐cancerous cells, including an integral role in glucose and fatty acid metabolism. In the heart, class 1 HDACs (HDAC1, 2, 3, and 8) regulate cell growth, and class 1‐specific inhibitors prevent cardiomyocyte hypertrophy. In the pancreas, HDAC inhibition protects β‐cells from apoptosis due to inflammatory insults. Because dysregulated cardiac metabolism, cardiac hypertrophy, and β‐cell apoptosis are complications of type 2 diabetes, we investigated the effects of a class 1 HDAC inhibitor on these outcomes. Type 2 diabetic db/db mice and C57BL/6J controls were treated with romidepsin (FK228), a chemotherapeutic class 1 HDAC inhibitor approved for T‐cell lymphoma, at a low dose (0.56 mg/kg twice a week) for eight weeks. Treatment with romidepsin did not affect heart mass in either genotype. However, in db/db mice romidepsin treatment increased body mass and reduced blood glucose to a level not significantly different from controls. The in vivo blood glucose reduction occurred independent of plasma insulin levels, suggesting that romidepsin is not an incretin; therefore, we investigated the role of class 1 HDACs in intracellular insulin signaling. Results showed that loss of HDAC2 by in vitro siRNA knockdown in AC16 human ventricular cardiomyocytes significantly amplified AKT phosphorylation in response to IGF‐1 treatment compared to IGF‐1 treatment alone. Cumulatively these results show that class 1 HDAC inhibition has anti‐diabetic effects in vivo and suggests that these effects are due to potentiation of intracellular insulin signalling. Support or Funding Information S.M. is supported by the Washington State University College of Pharmacy. E.J. is supported by the National Science Foundation Graduate Research Fellowship Program.