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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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published
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Diabetologia
volume
52
pages
271 - 280
publisher
Springer Verlag
external identifiers
  • wos:000262411200013
  • pmid:19023560
  • scopus:58149473940
ISSN
1432-0428
DOI
10.1007/s00125-008-1191-9
language
English
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yes
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e98bfc04-6dfd-435c-899e-55a164ca29f0 (old id 1271230)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19023560?dopt=Abstract
date added to LUP
2008-12-03 12:40:14
date last changed
2017-09-24 04:39:29
@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 Verlag},
  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},
  volume       = {52},
  year         = {2009},
}