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Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions.

Jacob McCann1, Megan Ellis1, Sean L McGee1

  • 1Metabolic Research Unit, School of Medicine, Deakin University , Waurn Ponds , Australia.

Islets
|May 22, 2019
PubMed
Summary

Class IIa Histone Deacetylases (HDACs) do not appear to impact beta-cell function or survival in normal or high glucose conditions. This suggests HDAC inhibitors are safe for treating type 2 diabetes.

Keywords:
HDAC-4HDAC-5Histone deacetylasebeta cellsdiabetesglucotoxicity

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Class IIa Histone Deacetylase (HDAC) inhibition shows therapeutic potential for skeletal and cardiac muscle health in chronic diseases like type 2 diabetes.
  • The role of Class IIa HDACs in pancreatic beta-cell function, crucial for glucose regulation, is currently unknown.

Purpose of the Study:

  • To investigate the role of Class IIa HDACs (HDAC-4 and -5) in pancreatic beta-cell function and survival under normal and hyperglycaemic conditions.
  • To determine if Class IIa HDACs are involved in beta-cell dysfunction associated with diabetes.

Main Methods:

  • INS-1E rat insulinoma cells were cultured in normal (11.1 mM) or hyperglycaemic (20 mM) glucose for 48 hours.
  • Gene and protein expression of HDAC-4 and -5 were analyzed.
  • Functional assays assessed insulin secretion, insulin mRNA levels, and apoptosis signaling following overexpression of wild-type or dominant-negative HDAC-4 and -5.

Main Results:

  • Hyperglycaemic conditions significantly reduced insulin secretion and increased apoptosis in INS-1E cells.
  • HDAC-4 and -5 transcript and protein levels were not altered by glucose conditions.
  • Modulating HDAC-4 and -5 activity or expression did not affect insulin secretion, insulin mRNA, or apoptosis.

Conclusions:

  • Class IIa Histone Deacetylases (HDAC-4 and -5) do not appear to play a significant physiological role in pancreatic beta-cells under normal or diabetic conditions.
  • The findings suggest that therapeutic strategies involving Class IIa HDAC inhibitors are unlikely to adversely affect beta-cell function, supporting their use in metabolic disease treatment.