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Karl Bacos

Karl Bacos

Assistant researcher

Karl Bacos

MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues β-cell dysfunction caused by Hdac7 upregulation

Author

  • Mahboubeh Daneshpajooh
  • Lena Eliasson
  • Karl Bacos
  • Charlotte Ling

Summary, in English

Aims: It has in recent years been established that epigenetic changes contribute to β-cell dysfunction and type 2 diabetes (T2D). For example, we have showed that the expression of histone deacetylase 7 (HDAC7) is increased in pancreatic islets of individuals with T2D and that increased levels of Hdac7 in β-cells impairs insulin secretion. The HDAC inhibitor MC1568 rescued this secretory impairment, suggesting that inhibitors specific for HDAC7 may be useful clinically in the treatment of T2D. The aim of the current study was to further explore HDAC7 as a novel therapeutic target in T2D. Methods: Hdac7 was overexpressed in clonal β-cells followed by the analysis of insulin secretion, mitochondrial function, as well as cell number and apoptosis in the presence or absence of MC1568. Furthermore, the effect of MC1568 on insulin secretion in human pancreatic islets from non-diabetic donors and donors with T2D was also studied. Results: Overexpression of Hdac7 in clonal β-cells significantly reduced insulin secretion, mitochondrial respiration, and ATP content, while it increased apoptosis. These impairments were all rescued by treatment with MC1568. The inhibitor also increased glucose-stimulated insulin secretion in islets from donors with T2D, while having no effect on islets from non-diabetic donors. Conclusions: HDAC7 inhibition protects β-cells from mitochondrial dysfunction and apoptosis, and increases glucose-stimulated insulin secretion in islets from human T2D donors. Our study supports specific HDAC7 inhibitors as novel options in the treatment of T2D.

Department/s

  • Diabetes - Epigenetics
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Islet Cell Exocytosis

Publishing year

2018-08-07

Language

English

Pages

1231-1235

Publication/Series

Acta Diabetologica

Volume

55

Issue

12

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Keywords

  • Epigenetics
  • HDAC inhibitor
  • Human pancreatic islets
  • Insulin secretion
  • MC1568
  • Type 2 diabetes

Status

Published

Research group

  • Diabetes - Epigenetics
  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 0940-5429