EXPRESSION OF HUMAN GLUT4 IN MICE RESULTS IN INCREASED INSULIN ACTION

Glucose metabolism was evaluated in transgenic mice expressing the hum an GLUT 4 glucose transporter. Fed GLUT 4 transgenic mice exhibited a 32 % and 56 % reduction in serum glucose and insulin and a 69 % and 33 % increase in non-esterified fatty acid and lactate levels, respectiv ely. Transgenic mice exhibited a significant increase in whole-body gl ucose disposal during a euglycaemic-hyperinsulinaemic clamp. Insulin-s timulated glucose uptake in isolated soleus muscles and adipocytes was greater in transgenic compared to control mice due to increased basal glucose uptake. Transgenic mice displayed increased glycogen levels i n liver and gastrocnemius muscle, and increased insulin-stimulated C-1 4-glycogen accumulation in isolated soleus muscle. We conclude that ov er-expression of the GLUT 4 glucose transporter in mice results in 1) an increase in whole-body glucose disposal and storage, and 2) an incr ease in both basal and insulin-stimulated glucose uptake and disposal in vitro. These changes resulted in the reduction of serum glucose and insulin levels. These results provide direct evidence that glucose tr ansport (and GLUT 4 per se) plays a significant role in regulating who le-body glucose homeostasis. Additionally, these data support the idea that pharmacological strategies directed at increasing the expression of GLUT 4 protein may have beneficial (hypoglycaemic) effects in the diabetic state.