Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-γ1

Abstract

Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). To determine whether troglitazone might enhance insulin action by stimulation of PPARgamma gene expression in muscle, total PPARgamma 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 microM). Troglitazone treatment increased PPARgamma mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 +/- 63 to 630 +/- 100 x 10(3) copies/microg total RNA, P = 0.003) and in nondiabetic control subjects (200 +/- 42 to 490 +/- 81, P = 0.003). PPARgamma protein levels in both diabetic (4.7 +/- 1.6 to 13.6 +/- 3.0 AU/10 microg protein, P < 0.02) and nondiabetic cells (7.4 +/- 1.0 to 12.7 +/- 1.8, P < 0.05) were also upregulated by troglitazone treatment. Increased PPARgamma 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, PPARdelta, myogenin, uncoupling protein-2, or sarcomeric alpha-actin protein. In summary, we showed that troglitazone markedly induces PPARgamma, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARgamma 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.