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

Fex, Malin LU ; Haemmerle, G ; Wierup, Nils LU ; Dekker Nitert, Marloes LU ; Rehn, M ; Ristow, M ; Zechner, R ; Sundler, Frank LU ; Holm, Cecilia LU and Eliasson, L , et al. (2009) In Diabetologia 52. p.271-280
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetologia
volume
52
pages
271 - 280
publisher
Springer
external identifiers
  • wos:000262411200013
  • pmid:19023560
  • scopus:58149473940
  • pmid:19023560
ISSN
1432-0428
DOI
10.1007/s00125-008-1191-9
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Diabetes and Celiac Unit (013241540), Molecular Endocrinology (013212018), Molecular Metabolism (013212001), Diabetes and Endocrinology (013241530), Neuroendocrine Cell Biology (013212008)
id
e98bfc04-6dfd-435c-899e-55a164ca29f0 (old id 1271230)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19023560?dopt=Abstract
date added to LUP
2016-04-04 08:49:04
date last changed
2024-04-12 23:05:07
@article{e98bfc04-6dfd-435c-899e-55a164ca29f0,
  abstract     = {{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.}},
  author       = {{Fex, Malin and Haemmerle, G and Wierup, Nils and Dekker Nitert, Marloes and Rehn, M and Ristow, M and Zechner, R and Sundler, Frank and Holm, Cecilia and Eliasson, L and Mulder, Hindrik}},
  issn         = {{1432-0428}},
  language     = {{eng}},
  pages        = {{271--280}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.}},
  url          = {{http://dx.doi.org/10.1007/s00125-008-1191-9}},
  doi          = {{10.1007/s00125-008-1191-9}},
  volume       = {{52}},
  year         = {{2009}},
}