Troglitazone Induces GLUT4 Translocation in L6 Myotubes
- Shin Yonemitsu,
- Haruo Nishimura,
- Mitsuyo Shintani,
- Ryou Inoue,
- Yuji Yamamoto,
- Hiroaki Masuzaki,
- Yoshihiro Ogawa,
- Kiminori Hosoda,
- Gen Inoue,
- Tatsuya Hayashi and
- Kazuwa Nakao
- Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10−5 mol/l) caused a substantial increase in the 2-deoxy-[3H]d-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 μmol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 × 10−6 mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-λ, PKC-β2, and PKC-ζ; or 5′AMP-activated protein kinase activity. α-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.
Address correspondence and reprint requests to Haruo Nishimura, MD, PhD, Department of Diabetes and Endocrinorosy, Osakahu Saiseikai Nakatsu Hospital 2-10-39 Shibata, Kitaku, Osaka 530-0012, Japan. E-mail:.
Received for publication 14 June 1999 and accepted in revised form 24 January 2001.
2-DG, 2-deoxy-[3H]d-glucose; α-MEM, α-minimal essential medium; AMPK, 5′AMP-activated protein kinase; CPM, crude plasma membrane; DTT, dithiothreitol; FBS, fetal bovine serum; KRPH, HEPES-buffered Krebs-Ringer phosphate; LM, light microsome; LPS, liposaccharide; PCR, polymerase chain reaction; PI, phosphatidylinositol; PKB, protein kinase B; PKC, protein kinase C; PMSF, phenylmethylsulfonyl fluoride; PPAR, peroxisome proliferator–activated receptor; RT, reverse transcription; TGZ, troglitazone.