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 microgram/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.
Tsao
T S
TS
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Burcelin
R
R
Katz
E B
EB
Huang
L
L
Charron
M J
MJ
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D003847:Deoxyglucose / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000096:biosynthesis; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*
D001786:Blood Glucose; D017931:DNA Primers; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D006003:Glycogen; D003847:Deoxyglucose; D005947:Glucose