ENHANCED PERIPHERAL GLUCOSE-UTILIZATION IN TRANSGENIC MICE EXPRESSINGTHE HUMAN GLUT4 GENE

Human GLUT4 protein expression in muscle and adipose tissues of transg enic mice decreases plasma insulin and glucose levels and improves glu cose tolerance compared with nontransgenic controls (Liu, M.-L., Gibbs , E. M., McCoid, S. C., Milici, A. J., Stukenbrok, H. A., McPherson, R . K., Treadway, J. L., and Pessin, J. E. (1993) Proc. Natl. Acad. Sci. U.S. A. 90, 11346-11350). We examined the basis of improved glycemic control in hGLUT4 transgenic mice by determining glucose homeostasis a nd metabolic profiles in vivo. Glucose turnover experiments indicated a 1.4-fold greater systemic glucose clearance in hGLUT4 mice relative to controls (p < 0.05), whereas hepatic glucose production was similar despite 26% lower (p < 0.05) glucose levels. Glucose infusion rate du ring an euglycemic-hyperinsulinemic clamp was e-fold greater (p < 0.05 ) in hGLUT4 mice versus controls, and skeletal muscle and heart glycog en content were increased 3-5-fold (p < 0.05). The increased periphera l glucose clearance in hGLUT4 mice was associated with increased (25-3 2%) basal and insulin-stimulated glucose transport rate in soleus musc le (p < 0.01), and increased muscle plasma membrane-associated GLUT4 p rotein. Fed hGLUT4 mice displayed 20-30% lower plasma glucose and insu lin levels (p < 0.05) and 43% elevated glucagon levels (p < 0.001) com pared with controls. Triglycerides, free fatty acids, and P-hydroxybut yrate were elevated 43-63% (p < 0.05) in hGLUT4 mice due to hypoinsuli nemia-induced lipolysis. Free fatty acids and P-hydroxybutyrate levels in hGLUT4 mice increased further upon fasting, and skeletal muscle gl ycogen levels decreased markedly compared with controls. The data demo nstrate that high level expression of hGLUT4 increases systemic glucos e clearance and muscle glucose utilization in vivo and also results in marked compensatory Lipolysis and muscle glycogenolysis during a fast .