The acute insulin sensitizing effects of troglitazone are mediated by AMPK activation and inhibition of pyruvate dehyrogenase activity

Abstract

This study investigated the acute effects of troglitazone (Tro) on glucose and fatty acid (FA) partitioning in skeletal muscle. Exposure of L6 myotubes to Tro for 1h resulted in ∼1.3‐ and ∼1.6‐fold increases in palmitate oxidation and CPT‐1 activity, respectively. Tro inhibited basal (∼25%) and insulin‐stimulated (∼35%) palmitate uptake but significantly increased basal (∼2.2‐fold) and insulin‐stimulated (∼2.7‐fold) glucose uptake. Inhibition of AMPK prevented the effects of Tro on palmitate oxidation and glucose uptake. Although Tro exerted an insulin sensitizing effect, it reduced basal and insulin‐stimulated rates of glycogen synthesis, incorporation of glucose into lipids, and glucose oxidation to values corresponding to ∼30%, ∼60%, and 30% of the controls, respectively. These effects were accompanied by an increase in basal and insulin‐stimulated phosphorylation of AktThr308, AktSer473, and GSK3α/β. Tro also powerfully suppressed pyruvate decarboxylation, which was followed by a significant increase in basal (∼3.5‐fold) and insulin‐stimulated (∼5.5‐fold) rates of lactate production. In summary, we provide novel evidence that Tro exerts acute insulin sensitizing effects by increasing FA oxidation, reducing FA uptake, suppressing pyruvate dehydrogenase activity, and shifting glucose metabolism towards lactate production in muscle cells. Funding was provided by NSERC, CIHR, and CDA.