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

TY - JOUR

T1 - A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

AU - Fex, M

AU - Haemmerle, G

AU - Wierup, N

AU - Dekker-Nitert, M

AU - Rehn, M

AU - Ristow, M

AU - Zechner, R

AU - Sundler, F

AU - Holm, C

AU - Eliasson, L

AU - Mulder, H

PY - 2009/2

Y1 - 2009/2

N2 - 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.

AB - 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.

KW - Adipose Tissue/enzymology

KW - Animals

KW - Area Under Curve

KW - Blood Glucose/metabolism

KW - Exocytosis/genetics

KW - Exons

KW - Glucose Tolerance Test

KW - Hyperglycemia/blood

KW - Insulin/secretion

KW - Insulin-Secreting Cells/enzymology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mutation

KW - Polymerase Chain Reaction

KW - RNA, Messenger/genetics

KW - Secretory Vesicles/enzymology

KW - Sterol Esterase/deficiency

U2 - 10.1007/s00125-008-1191-9

DO - 10.1007/s00125-008-1191-9

M3 - Journal article

C2 - 19023560

SN - 0012-186X

VL - 52

SP - 271

EP - 280

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -