Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects Theodore P. Ciaraldi 1 , Alice P.S. Kong 1 , Neelima V. Chu 1 , Dennis D. Kim 1 , Sunita Baxi 1 , Mattias Loviscach 1 , Ray Plodkowski 1 , Richard Reitz 2 , Michael Caulfield 2 , Sunder Mudaliar 1 and Robert R. Henry 1 1 VA San Diego Healthcare System and the Department of Medicine, University of California, San Diego, California 2 Quest Diagnostics, San Juan Capistrano, California Abstract Type 2 diabetic subjects failing glyburide therapy were randomized to receive additional therapy with either metformin (2,550 mg/day) or troglitazone (600 mg/day) for 3–4 months. Biopsies of subcutaneous abdominal adipose tissue were obtained before and after therapy. Glycemic control was similar with both treatments. Metformin treatment increased insulin-stimulated whole-body glucose disposal rates by 20% ( P < 0.05); the response to troglitazone was greater (44% increase, P < 0.01 vs. baseline, P < 0.05 vs. metformin). Troglitazone-treated subjects displayed a tendency toward weight gain (5 ± 2 kg, P < 0.05), increased adipocyte size, and increased serum leptin levels. Metformin-treated subjects were weight-stable, with unchanged leptin levels and reduced adipocyte size (to 84 ± 4% of control, P < 0.005). Glucose transport in isolated adipocytes from metformin-treated subjects was unaltered from pretreatment. Glucose transport in both the absence (321 ± 134% of pre-Rx, P < 0.05) and presence of insulin (418 ± 161%, P < 0.05) was elevated after troglitazone treatment. Metformin treatment had no effect on adipocyte content of GLUT1 or GLUT4 proteins. After troglitazone treatment, GLUT4 protein expression was increased twofold (202 ± 42%, P < 0.05). Insulin-stimulated serine phosphorylation of Akt was augmented after troglitazone (170 ± 34% of pre-Rx response, P < 0.05) treatment and unchanged by metformin. We conclude that the ability of troglitazone to upregulate adipocyte glucose transport, GLUT4 expression, and insulin signaling can contribute to its greater effect on whole-body glucose disposal. Footnotes Address correspondence and reprint requests to Dr. Robert R. Henry, Department of Medicine (V111G), VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161. E-mail: rrhenry{at}vapop.ucsd.edu . Received for publication 6 August 2001 and accepted in revised form 17 October 2001. T.P.C. and S.M. have received honoraria