IMPROVED GLUCOSE-TOLERANCE RESTORES INSULIN-STIMULATED AKT KINASE-ACTIVITY AND GLUCOSE-TRANSPORT IN SKELETAL-MUSCLE FROM DIABETIC GOTO-KAKIZAKI RATS

The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C protein kinase [RAC]) has recently been implicated to play a r ole in the signaling pathway to glucose transport. However, little is known concerning the regulation of Akt activity in insulin-sensitive t issues such as skeletal muscle. To explore the role of hyperglycemia o n Akt kinase activity in skeletal muscle, normal Wistar rats or Goto-K akizaki (GK) diabetic rats were treated with phlorizin. Phlorizin trea tment normalized fasting blood glucose and significantly improved gluc ose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the comp ound had no effect on glucose homeostasis. In soleus muscle from GK ra ts, maximal insulin-stimulated (120 nmol/l) Akt kinase activity was re duced by 68% (P < 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with Wistar rats. Importantly, the defects at the le vel of Akt kinase and glucose transport were completely restored by ph lorizin treatment. There was no significant difference in Akt kinase p rotein expression among the three groups. At a submaximal insulin conc entration (2.4 nmol/l), activity of Akt kinase and glucose transport w ere unaltered. In conclusion, improved glucose tolerance in diabetic G K rats by phlorizin treatment fully restored insulin-stimulated activi ty of Akt kinase and glucose transport. Thus, hyperglycemia may direct ly contribute to the development of muscle insulin resistance through alterations in insulin action on Akt kinase and glucose transport.