AKT1 KINASE AND DYNAMICS OF INSULIN-RESISTANCE IN DENERVATED MUSCLES IN-VIVO

Basal and insulin-stimulated activity of Akt1 kinase and uptake of 2-d eoxy-D-glucose (2-DG) were measured in soleus (slow-twitch) and planta ris (fast-twitch) muscles of rats at 1 and 3 days after sectioning the sciatic nerve in one hindlimb of the animals. At 1 day after surgery, the insulin-stimulated activity of Akt1 kinase in denervated soleus a nd plantaris muscles remained unchanged, but the insulin-stimulated 2- DG uptake by these muscles was reduced by 71 and 61%, respectively, co mpared with the corresponding muscles of the contralateral sham (contr ol) hindlimb. At 3 days, the insulin-stimulated activity of Akt1 kinas e in the denervated soleus and plantaris muscles was 86 and 71% lower, respectively, than in their sham counterparts. At this time point, th e denervated soleus muscles showed no increase in 2-DG uptake in respo nse to insulin. In contrast, the denervated plantaris muscle exhibited the same absolute level of insulin-stimulated 2-DG uptake as the sham plantaris muscle; however, the insulin-induced increment in 2-DG upta ke was reduced by 60%, whereas basal 2-DG uptake was increased by 251% compared with the sham plantaris muscle. None of the denervated muscl es showed a decrease in the abundance of Akt1 kinase. The results demo nstrate that the causes of insulin resistance in denervated muscles ar e dependent on time after surgery. Initially, they involve only mechan isms downstream of Akt1 kinase (day I), whereas at clay 3 they also in volve mechanisms upstream of, and including, Akt1 kinase.