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Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
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Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

Yukina Kawada1, Shun-Ichiro Asahara2, Yumiko Sugiura1

  • 1Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Plos One
|September 9, 2017
PubMed

Insights

Histone deacetylases regulate pancreatic beta cell function by controlling insulin receptor substrate 2 (IRS2) expression and activity. This epigenetic and protein modification impacts insulin signaling, offering potential therapeutic targets for type 2 diabetes.

Area of Science:

  • Molecular Endocrinology
  • Epigenetics
  • Diabetes Research

Background:

  • Insulin signaling is crucial for pancreatic beta cell mass regulation; its reduction is linked to diabetes development.
  • Mechanisms altering insulin signaling in beta cells and the role of epigenetics in diabetes remain unclear.
  • Insulin receptor substrate 2 (IRS2) is a key mediator of insulin signaling.

Purpose of the Study:

  • To investigate the epigenetic control of insulin receptor substrate 2 (IRS2) expression in pancreatic beta cells.
  • To elucidate the role of histone deacetylases (HDACs) in regulating IRS2 and insulin signaling.

Main Methods:

  • Analysis of IRS2 expression and insulin signaling in MIN6 mouse insulinoma cells.
  • Assessment of H3K9 acetylation status at the Irs2 promoter.
  • Treatment with histone deacetylase inhibitors and subsequent analysis of IRS2 expression, acetylation, and tyrosine phosphorylation.

Main Results:

  • IRS2 up-regulation and enhanced insulin signaling correlated with increased MIN6 cell proliferation.
  • H3K9 acetylation of the Irs2 promoter was positively associated with IRS2 expression.
  • HDAC inhibition increased IRS2 expression and lysine acetylation but decreased tyrosine phosphorylation and insulin signaling.

Conclusions:

  • Histone deacetylases regulate insulin signaling in pancreatic beta cells via epigenetic control of IRS2 expression (H3K9 acetylation) and protein modification (lysine acetylation).
  • These findings reveal novel pathways involving IRS2 regulation by HDACs, impacting beta cell function.
  • Identifying specific HDAC isoforms involved could provide therapeutic strategies for type 2 diabetes.

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