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Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene
J L Treadway1, D M Hargrove, N A Nardone
1Department of Metabolic Diseases, Pfizer Inc., Groton, CT 06340.
The Journal of Biological Chemistry
|November 25, 1994
Summary
Transgenic mice with human GLUT4 (hGLUT4) protein show improved glucose control and higher glucose uptake in muscles. Fasting these mice leads to increased lipolysis and muscle glycogen breakdown.
Area of Science:
- Metabolic research
- Molecular biology
- Physiology
Background:
- Human glucose transporter type 4 (hGLUT4) is crucial for insulin-stimulated glucose uptake in muscle and adipose tissue.
- Transgenic models are essential for studying gene function and metabolic regulation in vivo.
- Previous studies indicated that hGLUT4 expression improves glucose tolerance, but the underlying mechanisms require further investigation.
Purpose of the Study:
- To elucidate the mechanisms behind improved glycemic control in hGLUT4 transgenic mice.
- To analyze glucose homeostasis and metabolic profiles in hGLUT4 transgenic mice under fed and fasted conditions.
- To investigate the impact of enhanced hGLUT4 expression on glucose transport, glycogen storage, and lipolysis.
Main Methods:
- Glucose turnover experiments to assess systemic glucose clearance and hepatic glucose production.
- Euglycemic-hyperinsulinemic clamp studies to determine glucose infusion rates and insulin sensitivity.
- Measurement of glucose transport rates, GLUT4 protein levels, and glycogen content in skeletal muscle.
- Analysis of plasma levels of glucose, insulin, glucagon, triglycerides, free fatty acids, and beta-hydroxybutyrate.
Main Results:
- hGLUT4 mice exhibited a 1.4-fold greater systemic glucose clearance and a 2-fold higher glucose infusion rate during clamps.
- Skeletal muscle and heart glycogen content were significantly increased (3-5 fold) in hGLUT4 mice.
- Basal and insulin-stimulated glucose transport rates in soleus muscle increased by 25-32%, associated with higher muscle plasma membrane-associated GLUT4 protein.
- Fed hGLUT4 mice had lower plasma glucose and insulin levels but elevated glucagon and lipid metabolites due to lipolysis.
- Fasting exacerbated lipolysis and led to a marked decrease in skeletal muscle glycogen in hGLUT4 mice.
Conclusions:
- High-level expression of hGLUT4 enhances systemic glucose clearance and muscle glucose utilization in vivo.
- Increased hGLUT4 leads to compensatory lipolysis and muscle glycogenolysis during fasting.
- These findings provide critical insights into the regulation of glucose homeostasis and metabolic adaptation.