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Vol. 293, Issue 2, 487-493, May 2000

Troglitazone Directly Inhibits CO2 Production from Glucose and Palmitate in Isolated Rat Skeletal Muscle1

Clemens Fürnsinn, Barbara Brunmair, Susanne Neschen, Michael Roden and Werner Waldhäusl

Department of Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Vienna, Austria

Troglitazone is a nuclear peroxisome proliferator-activated receptor-gamma 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 < .0001) and palmitate (palmitate converted to CO2, nanomoles per gram per hour: control, 75 ± 5 versus troglitazone, 20 ± 2, P < .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 < .0001) and glucose transport ([3H]2-deoxyglucose transport, cpm per milligram per hour: control, 540 ± 46 versus troglitazone, 791 ± 61, P < .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 < .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.

1 This work was supported by Sankyo (Tokyo, Japan) and by the Austrian Science Fund (Grant P13049-MED).

0022-3565/00/2932-0487$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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