Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

PLoS One. 2017 Sep 8;12(9):e0184435. doi: 10.1371/journal.pone.0184435. eCollection 2017.

Abstract

Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Phosphorylation
  • Promoter Regions, Genetic
  • Signal Transduction* / drug effects

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Histone Deacetylases

Grants and funding

This work was supported by Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Shun-ichiro Asahara (S.A.) Grant number: 26461382; Uehara Memorial Foundation to Yoshiaki Kido (Y.K.) http://www.ueharazaidan.or.jp; Takeda Science Foundation to Naoko Hashimoto (N.H.) http://www.takeda-sci.or.jp; Suzuken Memorial Foundation to Naoko Hashimoto (N.H.) http://www.suzukenzaidan.or.jp; Yamaguchi Endocrine Research Foundation to Naoko Hashimoto (N.H.) http://www.yamaguchi-endocrine.org; Honjo International Scholarship Foundation to Shun-ichiro Asahara (S.A.) http://www.hisf.or.jp; and Hyogo Science and Technology Association to Shun-ichiro Asahara (S.A.) http://hyogosta.jp/reconstruction/jyosei.