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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.

Author

  • Malin Fex
  • G Haemmerle
  • Nils Wierup
  • Marloes Dekker Nitert
  • M Rehn
  • M Ristow
  • R Zechner
  • Frank Sundler
  • Cecilia Holm
  • L Eliasson
  • Hindrik Mulder

Summary, in English

AIMS/HYPOTHESIS: The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. METHODS: To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. RESULTS: We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. CONCLUSIONS/INTERPRETATION: Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipid-derived signal essential for normal insulin secretion.

Department/s

  • Diabetes and Celiac Unit
  • Department of Experimental Medical Science
  • Genomics, Diabetes and Endocrinology
  • Molecular Endocrinology

Publishing year

2009

Language

English

Pages

271-280

Publication/Series

Diabetologia

Volume

52

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes and Celiac Unit
  • Genomics, Diabetes and Endocrinology
  • Molecular Endocrinology

ISBN/ISSN/Other

  • ISSN: 1432-0428