GLUCOSE-TRANSPORT ACTIVITY IN SKELETAL-MUSCLES FROM TRANSGENIC MICE OVEREXPRESSING GLUT1 - INCREASED BASAL TRANSPORT IS ASSOCIATED WITH A DEFECTIVE RESPONSE TO DIVERSE STIMULI THAT ACTIVATE GLUT4

Glucose transport activity was examined in transgenic mice overexpress ing the human GLUT1 glucose transporter in skeletal muscles. Basal tra nsport activity measured in vitro with the glucose analog 2-deoxy-D-gl ucose (1 mM) was increased 2-8-fold in four different muscle preparati ons. Incubation of muscles from control nontransgenic littermates with a maximally effective concentration of insulin or with insulin-like g rowth factor-1 resulted in glucose transport rates that were 2-3-fold higher than basal. In contrast, insulin did not stimulate glucose tran sport activity in three different muscle preparations from transgenic animals; insulin-like growth factor-1 was similarly ineffective. Activ ation of System A amino acid transport activity (measured with the non metabolizable analog alpha-methylaminoisobutyrate) by insulin was not impaired in muscles from transgenic mice, indicating that the defect d oes not involve the insulin receptor. In skeletal muscle, glucose tran sport can be activated by muscle contractions or hypoxia via a pathway separate from that activated by insulin. Incubation of muscles under hypoxic conditions or stimulation of muscles to contract in situ did n ot increase glucose transport activity in muscles from GLUT1-overexpre ssing mice, in contrast to the stimulatory effects measured in muscles from control animals. These data suggest that increased glucose flux per se into skeletal muscle results in resistance of GLUT4 to activati on by insulin and various other stimuli that activate glucose transpor t by mechanisms distinct from that of insulin, GLUT1-overexpressing mi ce thus provide a new model system for studying the effects of glucose -induced resistance to activation of glucose transport.