AIMS/HYPOTHESIS: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor gamma receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. METHODS: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK alpha1/alpha2 siRNA. RESULTS: Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5- and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. CONCLUSIONS/ INTERPRETATION: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.
AIMS/HYPOTHESIS: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor gamma receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. METHODS: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK alpha1/alpha2 siRNA. RESULTS:Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5- and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. CONCLUSIONS/ INTERPRETATION: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.
Authors: Jason K Kim; Jonathan J Fillmore; Oksana Gavrilova; Lily Chao; Takamasa Higashimori; Hyejeong Choi; Hyo-Jeong Kim; Chunli Yu; Yan Chen; Xianqin Qu; Martin Haluzik; Marc L Reitman; Gerald I Shulman Journal: Diabetes Date: 2003-06 Impact factor: 9.461
Authors: Andrea L Hevener; Weimin He; Yaacov Barak; Jamie Le; Gautam Bandyopadhyay; Peter Olson; Jason Wilkes; Ronald M Evans; Jerrold Olefsky Journal: Nat Med Date: 2003-11-16 Impact factor: 53.440
Authors: Barbara Brunmair; Katrin Staniek; Florian Gras; Nicole Scharf; Aleksandra Althaym; Renate Clara; Michael Roden; Erich Gnaiger; Hans Nohl; Werner Waldhäusl; Clemens Fürnsinn Journal: Diabetes Date: 2004-04 Impact factor: 9.461
Authors: Kay Barnes; Jean C Ingram; Omar H Porras; L Felipe Barros; Emma R Hudson; Lee G D Fryer; Fabienne Foufelle; David Carling; D Grahame Hardie; Stephen A Baldwin Journal: J Cell Sci Date: 2002-06-01 Impact factor: 5.285
Authors: Vitor A Lira; Dana L Brown; Ana K Lira; Andreas N Kavazis; Quinlyn A Soltow; Elizabeth H Zeanah; David S Criswell Journal: J Physiol Date: 2010-07-19 Impact factor: 5.182
Authors: Boubacar Benziane; Marie Björnholm; Sergej Pirkmajer; Reginald L Austin; Olga Kotova; Benoit Viollet; Juleen R Zierath; Alexander V Chibalin Journal: J Biol Chem Date: 2012-05-18 Impact factor: 5.157
Authors: Charles W Bolten; Patrick M Blanner; William G McDonald; Nicholas R Staten; Richard A Mazzarella; Graciela B Arhancet; Martin F Meier; David J Weiss; Patrick M Sullivan; Alexander E Hromockyj; Rolf F Kletzien; Jerry R Colca Journal: Gene Regul Syst Bio Date: 2007-09-17