A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.
OBJECTIVE
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
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.
Fex
M
M
Department of Clinical Sciences, Clinical Research Centre , Malmö University Hospital (UMAS), Malmö, Sweden. malin.fex@med.lu.se
Haemmerle
G
G
Wierup
N
N
Dekker-Nitert
M
M
Rehn
M
M
Ristow
M
M
Zechner
R
R
Sundler
F
F
Holm
C
C
Eliasson
L
L
Mulder
H
H
D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics; D005091:Exons; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D022142:Secretory Vesicles / Q000201:enzymology; D002787:Sterol Esterase / Q000172:deficiency* / Q000235:genetics*
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D002787:Sterol Esterase