ENHANCED INSULIN ACTION DUE TO TARGETED GLUT4 OVEREXPRESSION EXCLUSIVELY IN MUSCLE

Dysregulation of GLUT4, the insulin-responsive glucose transporter, is associated with insulin resistance in skeletal muscle. Although skele tal 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 trans genic mice that overexpresses GLUT4 in skeletal muscle, We demonstrate that restricted overexpression of GLUT4 in fast-twitch skeletal muscl es of myosin light chain (MLC)-GLUT4 transgenic mice induces a 2.5-fol d increase in insulin-stimulated 2-deoxyglucose uptake in transgene-ov erexpressing 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 tr ansport is partly rate-limiting for glycogen synthesis, At the whole-b ody level, insulin-stimulated glucose turnover is increased 2.5-fold i n 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 mu g/l), whereas normal fasting glycem ia 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) w ith normal insulin levels, Fasting plasma lactate levels are elevated in both age groups (50-100%). Additionally, lipid metabolism is affect ed by skeletal muscle GLUT4 overexpression, This is indicated by chang es in plasma free fatty acid and beta-hydroxybutyrate levels, These st udies underscore the importance of GLUT4 in the regulation of glucose homeostasis and its interaction with lipid metabolism.