Activation of AMP-activated protein kinase, inhibition of pyruvate dehydrogenase activity, and redistribution of substrate partitioning mediate the acute insulin-sensitizing effects of troglitazone in skeletal muscle cells
✍ Scribed by S. Fediuc; A.S. Pimenta; M.P. Gaidhu; R.B. Ceddia
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 199 KB
- Volume
- 215
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
The aim of this study was to investigate the acute effects of troglitazone on several pathways of glucose and fatty acid (FA) partitioning and the molecular mechanisms involved in these processes in skeletal muscle. Exposure of L6 myotubes to troglitazone for 1 h significantly increased phosphorylation of AMPK and ACC, which was followed by ∼30% and ∼60% increases in palmitate oxidation and carnitine palmitoyl transferase‐1 (CPT‐1) activity, respectively. Troglitazone inhibited basal (∼25%) and insulin‐stimulated (∼35%) palmitate uptake but significantly increased basal and insulin‐stimulated glucose uptake by ∼2.2‐ and 2.7‐fold, respectively. Pharmacological inhibition of AMPK completely prevented the effects of troglitazone on palmitate oxidation and glucose uptake. Interestingly, even though troglitazone 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 Akt~Thr308~, Akt~Ser473~, and GSK3α/β. Troglitazone 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 by muscle cells. In summary, we provide novel evidence that troglitazone exerts acute insulin sensitizing effects by increasing FA oxidation, reducing FA uptake, suppressing pyruvate dehydrogenase activity, and shifting glucose metabolism toward lactate production in muscle cells. These effects seem to be at least partially dependent on AMPK activation and may account for potential acute PPAR‐γ‐independent anti‐diabetic effects of thiazolidinediones in skeletal muscle. J. Cell. Physiol. 215: 392–400, 2008. © 2007 Wiley‐Liss, Inc.