TY - JOUR
T1 - Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle
AU - Tsao, Tsu Shuen
AU - Burcelin, Rémy
AU - Katz, Ellen B.
AU - Huang, Lily
AU - Charron, Maureen J.
PY - 1996/1
Y1 - 1996/1
N2 - Dysregulation of GLUT4, the insulin-responsive glucose transporter, is associated with insulin resistance in skeletal muscle. Although skeletal muscle is the major target of insulin action, muscle GLUT4 has not been linked causally to whole-body insulin sensitivity and regulation of glucose homeostasis. To address this, we generated a line of transgenic mice that overexpresses GLUT4 in skeletal muscle. We demonstrate that restricted overexpression of GLUT4 in fast-twitch skeletal muscles of myosin light chain (MLC)-GLUT4 transgenic mice induces a 2.5-fold increase in insulin-stimulated 2-deoxyglucose uptake in transgene-overexpressing cells. Consequently, glycogen content is increased in the fast-twitch skeletal muscles under insulin action (5.75 ± 1.02 vs. 3.24 ± 0.26 mg/g). This indicates that insulin-stimulated glucose transport is partly rate-limiting for glycogen synthesis. At the whole-body level, insulin-stimulated glucose turnover is increased 2.5-fold in unconscious MLC-GLUT4 mice. Plasma glucose and insulin levels in MLC-GLUT4 mice are altered as a result of increased insulin action. In 2- to 3-month-old MLC-GLUT4 mice, fasting insulin levels are decreased (0.43 ± 0.05 vs. 0.74 ± 0.10 μg/l), whereas normal fasting glycemia is maintained. Conversely, 7- to 9-month-old MLC-GLUT4 mice exhibit decreased fasting glycemia (5.75 ± 0.73 vs. 8.11 ± 0.57 mmol/l) with normal insulin levels. Fasting plasma lactate levels are elevated in both age groups (50- 100%). Additionally, lipid metabolism is affected by skeletal muscle GLUT4 overexpression. This is indicated by changes in plasma free fatty acid and β-hydroxybutyrate levels. These studies underscore the importance of GLUT4 in the regulation of glucose homeostasis and its interaction with lipid metabolism.
AB - Dysregulation of GLUT4, the insulin-responsive glucose transporter, is associated with insulin resistance in skeletal muscle. Although skeletal muscle is the major target of insulin action, muscle GLUT4 has not been linked causally to whole-body insulin sensitivity and regulation of glucose homeostasis. To address this, we generated a line of transgenic mice that overexpresses GLUT4 in skeletal muscle. We demonstrate that restricted overexpression of GLUT4 in fast-twitch skeletal muscles of myosin light chain (MLC)-GLUT4 transgenic mice induces a 2.5-fold increase in insulin-stimulated 2-deoxyglucose uptake in transgene-overexpressing cells. Consequently, glycogen content is increased in the fast-twitch skeletal muscles under insulin action (5.75 ± 1.02 vs. 3.24 ± 0.26 mg/g). This indicates that insulin-stimulated glucose transport is partly rate-limiting for glycogen synthesis. At the whole-body level, insulin-stimulated glucose turnover is increased 2.5-fold in unconscious MLC-GLUT4 mice. Plasma glucose and insulin levels in MLC-GLUT4 mice are altered as a result of increased insulin action. In 2- to 3-month-old MLC-GLUT4 mice, fasting insulin levels are decreased (0.43 ± 0.05 vs. 0.74 ± 0.10 μg/l), whereas normal fasting glycemia is maintained. Conversely, 7- to 9-month-old MLC-GLUT4 mice exhibit decreased fasting glycemia (5.75 ± 0.73 vs. 8.11 ± 0.57 mmol/l) with normal insulin levels. Fasting plasma lactate levels are elevated in both age groups (50- 100%). Additionally, lipid metabolism is affected by skeletal muscle GLUT4 overexpression. This is indicated by changes in plasma free fatty acid and β-hydroxybutyrate levels. These studies underscore the importance of GLUT4 in the regulation of glucose homeostasis and its interaction with lipid metabolism.
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U2 - 10.2337/diab.45.1.28
DO - 10.2337/diab.45.1.28
M3 - Article
C2 - 8522056
AN - SCOPUS:0030069588
SN - 0012-1797
VL - 45
SP - 28
EP - 36
JO - Diabetes
JF - Diabetes
IS - 1
ER -