Effects of troglitazone on substrate storage and utilization in insulin-resistant rats

Elevated serum and tissue lipid stores are associated with skeletal muscle insulin resistance and diminished glucose-stimulated insulin secretion, the hallmarks of type 2 diabetes. We studied the effects of 6-wk treatment wit h the insulin sensitizer troglitazone on substrate storage and utilization in lean control and Zucker diabetic fatty (ZDF) rats. Troglitazone prevente d development of diabetes and lowered serum triglycerides (TG) in ZDF rats. Soleus muscle glycogen and TG content were elevated twofold in untreated Z DF rats, and both were normalized by troglitazone to lean control levels (P < 0.05). Troglitazone also normalized insulin-stimulated glucose uptake as well as basal and insulin-stimulated glycogen synthesis, implying increase d skeletal muscle glycogen turnover. The proportion of active pyruvate dehy drogenase (PDH) in soleus muscle was reduced in ZDF relative to lean contro l rat muscle (16 +/- 2 vs. 21 +/- 2%) but was restored by troglitazone trea tment (30 +/- 3%). Increased PDH activation was associated with a 70% incre ase ill glucose oxidation. Muscle lipoprotein lipase activity was decreased by 35% in ZDF compared with lean control rats and was increased twofold by troglitazone. Palmitate oxidation and incorporation into TG were higher in ZDF relative to lean control rats but were unaffected by troglitazone trea tment. Troglitazone decreased the incorporation of glucose into the acyl gr oup of TG by 60% in ZDF rats. In summary, ZDF rats demonstrate increased sk eletal muscle glycogen and TG stores, both of which were reduced by troglit azone treatment. Troglitazone appears to increase both glycogen and TG turn over in skeletal muscle. Normalization of PDH activity and decreased glucos e incorporation into acyl TG may underlie the improvements in intracellular substrate utilization and energy stores, which lead to decreased serum TG and glucose.