Phenotype of transgenic mice overexpressing GLUT4 and hexokinase II in muscle.

To optimize glucose utilization, double transgenic mice were created by crossing mice overexpressing glucose transporter GLUT4 with mice overexpressing hexokinase (HKII) in muscle. Transgenic mice overexpressing GLUT4 alone have exhibited improvements in glucose tolerance and insulin action. In vitro studies of hexose uptake in soleus muscle from transgenic mice suggested that GLUT4 was limiting the glucose flux except at high glucose concentration, where hexokinase became the limiting step. In vivo, glucose tolerance was similar in GLUT4 and GLUT4/HKII mice, although stimulated plasma insulin values were significantly lower in the latter group. Insulin tolerance tests performed in diabetic GLUT4 vs. diabetic GLUT4/HKII transgenic mice yielded identical results. Again, endogenous insulin in GLUT4/HKII mice during a mild hyperglycemic clamp was stimulated by only two- vs. fourfold in GLUT4 mice. Although the overexpression of HKII alone resulted in increased glucose utilization in several muscles, the overexpression of GLUT4 plus HKII did not augment basal or stimulated in vivo glucose utilization compared to GLUT4 overexpression. In conclusion, GLUT4 is rate limiting for muscle glucose utilization but HKII might be important under hyperglycemia. The addition of HKII to GLUT4 overexpression is not sufficient to further augment glucose tolerance or insulin action. In GLUT4/HKII double transgenic mice, glucose clearance is tempered by a low insulin stimulated level.