TY - JOUR T1 - Troglitazone Directly Inhibits CO<sub>2</sub> Production from Glucose and Palmitate in Isolated Rat Skeletal Muscle JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 487 LP - 493 VL - 293 IS - 2 AU - Clemens Fürnsinn AU - Barbara Brunmair AU - Susanne Neschen AU - Michael Roden AU - Werner Waldhäusl Y1 - 2000/05/01 UR - http://jpet.aspetjournals.org/content/293/2/487.abstract N2 - Troglitazone is a nuclear peroxisome proliferator-activated receptor-γ agonist with insulin-sensitizing properties that has been introduced for the treatment of type 2 diabetes. To further elucidate its mechanism of action, this study examined direct troglitazone effects on glucose and palmitate utilization in isolated rat soleus muscle. Exposure of muscle specimens for 25 h to 5 μmol/liter troglitazone resulted in the distinct inhibition of insulin-stimulated mitochondrial fuel oxidation as indicated by decreased rates of CO2 produced from glucose (glucose converted to CO2, nanomoles per gram per hour: control, 1461 ± 192 versus troglitazone, 753 ± 80,P &lt; .0001) and palmitate (palmitate converted to CO2, nanomoles per gram per hour: control, 75 ± 5 versus troglitazone, 20 ± 2, P &lt; .0001). Blunted fuel oxidation was accompanied by increased rates of anaerobic glycolysis (lactate release, micromoles per gram per hour: control, 17.3 ± 1.0 versus troglitazone, 49.2 ± 2.7,P &lt; .0001) and glucose transport ([3H]2-deoxyglucose transport, cpm per milligram per hour: control, 540 ± 46 versus troglitazone, 791 ± 61,P &lt; .0001), as well as by decreased rates of glycogen synthesis (glucose incorporation into glycogen, micromoles per gram per hour: control, 2.00 ± 0.26 versus troglitazone, 1.02 ± 0.13, P &lt; .001). Such shift toward anaerobic glucose utilization also was seen in the absence of insulin and with short-term troglitazone exposure for 90 min, indicating an underlying mechanism that is rapid and independent of concomitant insulin stimulation. The results demonstrate direct and acute inhibition of fuel oxidation to CO2 by troglitazone in rat skeletal muscle in vitro. The American Society for Pharmacology and Experimental Therapeutics ER -