TROGLITAZONE EFFECTS ON GENE-EXPRESSION IN HUMAN SKELETAL-MUSCLE OF TYPE-II DIABETES INVOLVE UP-REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA

Troglitazone, besides improving insulin action in insulin-resistant su bjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma). To determine wheth er troglitazone might enhance insulin action by stimulation of PPAR ga mma gene expression in muscle, total PPAR gamma messenger RNA (mRNA), and protein were determined in skeletal muscle cultures hom nondiabeti c control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days +/- troglitazone, 11.5 mu M). Trogl itazone treatment increased PPAR gamma mRNA levels up to S-fold in mus cle cultures from type II diabetics (277 +/- 63 to 630 +/- 100 x 10(3) copies/mu g total RNA, P = 0.003) and in nondiabetic control subjects (200 +/- 42 to 490 +/- 81, P = 0.003). PPAR gamma protein levels in b oth diabetic (4.7 +/- 1.6 to 13.6 +/- 3.0 AU/10 mu g protein, P < 0.02 ) and nondiabetic cells (7.4 +/- 1.0 to 12.7 +/- 1.8, P < 0.05) were a lso upregulated by troglitazone treatment. Increased PPAR gamma was as sociated with stimulation of human adipocyte lipid binding protein (AL BP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPAR delta, myoge nin, uncoupling protein-2, or sarcomeric alpha-actin protein. In summa ry, we showed that troglitazone markedly induces PPAR gamma, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and typ e II diabetic subjects. Increased expression of PPAR gamma protein and other genes involved in glucose and lipid metabolism in skeletal musc le may account, in part, for the insulin sensitizing effects of trogli tazone in type II diabetes.