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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2830-2835
Copyright © 1998 by The Endocrine Society

Original Studies

Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-{gamma}1

Kyong Soo Park, Theodore P. Ciaraldi, Kristin Lindgren, Leslie Abrams-Carter, Sunder Mudaliar, Svetlana E. Nikoulina, Sherrie R. Tufari, Jacques H. Veerkamp, Antonio Vidal-Puig2 and Robert R. Henry

Department of Medicine, University of California (K.S.P., T.P.C., K.L., L.A.-C., S.M., S.E.N., R.R.H.), San Diego, La Jolla, California 92093; Veterans Affairs Medical Center, San Diego (K.S.P., T.P.C., K.L., L.A.-C., S.M., S.E.N., R.R.H.), San Diego, California 92161; Department of Signal Transduction, Parke Davis Pharmaceutical Research (S.R.T.), Ann Arbor, Michigan 48105; Department of Biochemistry, Katholieke Universiteit Nijmogen (J.H.V.), Nijmegen, The Netherlands; and Division of Endocrinology, Beth Israel Deaconess Medical Center (A.V.-P.), Boston Massachusetts 02215

Address all correspondence and requests for reprints to: Robert R. Henry, Veterans Affairs Medical Center, San Diego (V111G), 3350 La Jolla Village Drive, San Diego, California 92161. E-mail: rrhenry{at}vapop.ucsd.edu

Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). To determine whether troglitazone might enhance insulin action by stimulation of PPAR{gamma} gene expression in muscle, total PPAR{gamma} messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days ± troglitazone, 11.5 µM). Troglitazone treatment increased PPAR{gamma} mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 ± 63 to 630 ± 100 x 103 copies/µg total RNA, P = 0.003) and in nondiabetic control subjects (200 ± 42 to 490 ± 81, P = 0.003). PPAR{gamma} protein levels in both diabetic (4.7 ± 1.6 to 13.6 ± 3.0 AU/10 µg protein, P < 0.02) and nondiabetic cells (7.4 ± 1.0 to 12.7 ± 1.8, P < 0.05) were also up-regulated by troglitazone treatment. Increased PPAR{gamma} was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPAR{delta}, myogenin, uncoupling protein-2, or sarcomeric {alpha}-actin protein. In summary, we showed that troglitazone markedly induces PPAR{gamma}, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPAR{gamma} protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.




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