Aim: 

Recently it was demonstrated that the ketone body-hydroxybutyrate (BOH) inhibits insulin-mediated glucose transport in isolated oxidative muscle. The purpose of this study was to determine if repeated contractions or pharmacological activation of AMP-dependent protein kinase (using AICAR) could reverse the insulin resistance induced by BOH.

Methods: 

Isolated mouse soleus muscle was incubated in vitro in the absence or presence of 5 mM BOH for ~ 20 h.

Results: 

Following prolonged incubation, insulin increased 2-deoxyglucose glucose (2 -DG) uptake 3-fold and BOH blocked this insulin-mediated increase. A series of repeated con tractions in freshly isolated muscles did not reverse the insulin resistance induced by pro longed exposure to BOH. Addition of 2 mM AICAR during the last 2 h of prolonged incubation did to some extent restore the insulin-mediated 2-DG uptake. This AICAR-mediated reversal o f the insulin resistance was not associated with a restoration of the insulin-mediated phosphorylation of Akt/protein kinase B. However, AICAR did restore the insulin-induced phosphorylation of the Akt substrate, AS160.

Conclusion: 

These data demonstrate that AICAR can reverse the negative effect of BOH on insulin-mediated glucose uptake and that this is attributed to activation of a late step in insulin signaling.