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.

Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity.

Author

  • Siri Malmgren
  • Peter Spégel
  • Anders Danielsson
  • Cecilia Nagorny
  • Lotta Andersson
  • Marloes Dekker Nitert
  • Martin Ridderstråle
  • Hindrik Mulder
  • Charlotte Ling

Summary, in English

Lipotoxicity is a presumed pathogenetic process whereby elevated circulating and stored lipids in Type 2 Diabetes cause pancreatic β-cell failure. To resolve the underlying molecular mechanisms, we exposed clonal INS-1 832/13 β-cells to palmitate for 48 h. We observed elevated basal insulin secretion but impaired glucose-stimulated insulin secretion in palmitate-exposed cells. Glucose utilization was unchanged, palmitate oxidation increased, and oxygen consumption impaired. Removal of palmitate from the clonal INS-1 832/13 β-cells largely recovered all of the lipid-induced functional changes. Metabolite profiling revealed profound but reversible increases in cellular lipids. Glucose-induced increases in tricarboxylic acid cycle intermediates were attenuated by exposure to palmitate. Analysis of gene expression by microarray showed increased expression of 982 genes and decreased expression of 1032 genes after exposure to palmitate. Increases were seen in pathways for steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids; decreases occurred in the aminoacyl-tRNA-synthesis pathway. The activity of histone-modifying enzymes and histone modifications of differentially expressed genes were reversibly altered upon exposure to palmitate. Thus, Insig1, Lss, Peci, Idi1, Hmgcs1 and Casr were subject to epigenetic regulation. Our analyses demonstrate that coordinate changes in histone modifications, mRNA levels and metabolite profiles accompanied functional adaptations of clonal β-cells to lipotoxicity. It is highly likely that these changes are pathogenetic, accounting for loss of glucose responsiveness and perturbed insulin secretion.

Department/s

  • Diabetes - Molecular Metabolism
  • Diabetes - Epigenetics
  • Medicine, Lund
  • Diabetes - Clinical Obesity
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2013

Language

English

Pages

11973-11987

Publication/Series

Journal of Biological Chemistry

Volume

288

Issue

17

Document type

Journal article

Publisher

ASBMB

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Molecular Metabolism
  • Diabetes - Epigenetics
  • Diabetes - Clinical Obesity

ISBN/ISSN/Other

  • ISSN: 1083-351X