GERMLINE MANIPULATION OF GLUCOSE-HOMEOSTASIS VIA ALTERATION OF GLUCOSE-TRANSPORTER LEVELS IN SKELETAL-MUSCLE

Transgenic mice were constructed that overexpress the human Glut1 gluc ose transporter in skeletal muscle. Transcription of the human Glut1 c DNA was driven by the rat myosin light chain 2 promoter. Soleus and qu adriceps muscles from transgenic mice expressed increased levels of Gl ut1 protein relative to muscles obtained from nontransgenic littermate s, but there was no difference in the level of Glut4 protein between t he two groups. Skeletal muscles isolated from the transgenic animals e xhibited 3-4-fold increases in basal glucose uptake relative to muscle s obtained from nontransgenic littermates. Muscles isolated from nontr ansgenic littermates exhibited 2-3-fold increases in glucose transport after incubation in the presence of insulin, but no insulin-stimulate d increase in transport was observed in the muscles of transgenic mice . Plasma glucose levels were reduced by 18 and 30%, respectively, in f ed and fasted transgenic mice relative to their nontransgenic siblings , but insulin and glucagon levels were not significantly different bet ween the two groups. Glucose disposal following an oral glucose load w as markedly enhanced in the transgenic animals, and plasma lactate and beta-OH-butyrate levels were elevated in both fed and fasted transgen ic mice. These data strongly support the hypothesis that glucose trans port plays a key role in whole body glucose homeostasis. They also dem onstrate that the level of a glucose transporter in skeletal muscle ca n significantly influence the blood glucose set point and alter the le vels of other fuel metabolites in the blood.