title: 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.
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 approximately 30% and approximately 60% increases in palmitate oxidation and carnitine palmitoyl transferase-1 (CPT-1) activity, respectively. Troglitazone inhibited basal ( approximately 25%) and insulin-stimulated ( approximately 35%) palmitate uptake but significantly increased basal and insulin-stimulated glucose uptake by approximately 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 approximately 30%, approximately 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 GSK3alpha/beta. Troglitazone also powerfully suppressed pyruvate decarboxylation, which was followed by a significant increase in basal ( approximately 3.5-fold) and insulin-stimulated ( approximately 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-gamma-independent anti-diabetic effects of thiazolidinediones in skeletal muscle.
authors.affiliation: School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Fediuc
authors.forename: A S
authors.initials: AS
authors.lastname: Pimenta
authors.forename: M P
authors.initials: MP
authors.lastname: Gaidhu
authors.forename: R B
authors.initials: RB
authors.lastname: Ceddia
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects; D000077288:Troglitazone
chemical_list: D002839:Chromans; D005227:Fatty Acids; D007328:Insulin; D009097:Multienzyme Complexes; D010168:Palmitates; D011720:Pyrazoles; D011743:Pyrimidines; D011768:Pyruvate Dehydrogenase Complex; D045162:Thiazolidinediones; C516138:dorsomorphin; D019344:Lactic Acid; D002334:Carnitine O-Palmitoyltransferase; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D000077288:Troglitazone; D005947:Glucose