Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Alexander Perfilyev

Assistant researcher

Default user image.

Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets

Author

  • Elin Hall
  • Josefine Jönsson
  • Jones K. Ofori
  • Petr Volkov
  • Alexander Perfilyev
  • Marloes Dekker Nitert
  • Lena Eliasson
  • Charlotte Ling
  • Karl Bacos

Summary, in English

Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genomewide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Epigenetics
  • Diabetes - Islet Cell Exocytosis
  • Department of Experimental Medical Science

Publishing year

2019-10

Language

English

Pages

1965-1974

Publication/Series

Diabetes

Volume

68

Issue

10

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Cell and Molecular Biology
  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Epigenetics
  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 0012-1797