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 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 mu g/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 beta-hydroxybutyrate levels, These studies underscore the importance of GLUT4 in the regulation of glucose homeostasis and its interaction with lipid metabolism.