Troglitazone directly inhibits CO2 production from glucose and palmitate in isolated rat skeletal muscle

Troglitazone is a nuclear peroxisome proliferator-activated receptor-gamma agonist with insulin-sensitizing properties that has been introduced for th e treatment of type 2 diabetes. To further elucidate its mechanism of actio n, this study examined direct troglitazone effects on glucose and palmitate utilization in isolated rat soleus muscle. Exposure of muscle specimens fo r 25 h to 5 mu mol/liter troglitazone resulted in the distinct inhibition o f insulin-stimulated mitochondrial fuel oxidation as indicated by decreased rates of CO2 produced from glucose (glucose converted to CO2, nanomoles pe r gram per hour: control, 1461 +/- 192 versus troglitazone, 753 +/- 80, P < .0001) and palmitate (palmitate converted to CO2, nanomoles per gram per h our: control, 75 +/- 5 versus troglitazone, 20 +/- 2, P < .0001). Blunted f uel oxidation was accompanied by increased rates of anaerobic glycolysis (l actate release, micromoles per gram per hour: control, 17.3 +/- 1.0 versus troglitazone, 49.2 +/- 2.7, P < .0001) and glucose transport ([H-3]2-deoxyg lucose transport, cpm per milligram per hour: control, 540 +/- 46 versus tr oglitazone, 791 +/- 61, P < .0001), as well as by decreased rates of glycog en synthesis (glucose incorporation into glycogen, micromoles per gram per hour: control, 2.00 +/- 0.26 versus troglitazone, 1.02 +/- 0.13, P < .001). Such shift toward anaerobic glucose utilization also was seen in the absen ce of insulin and with short-term troglitazone exposure for 90 min, indicat ing an underlying mechanism that is rapid and independent of concomitant in sulin stimulation. The results demonstrate direct and acute inhibition of f uel oxidation to CO2 by troglitazone in rat skeletal muscle in vitro.