ACUTE EFFECT OF TROGLITAZONE ON GLUCOSE-METABOLISM IN THE ABSENCE OR PRESENCE OF INSULIN IN PERFUSED RAT HINDLIMB

Troglitazone (CS-045) is a new type of antidiabetic agent that decreas es plasma glucose by enhancing insulin action in insulin-resistant dia betic animals and non-insulin-dependent diabetes mellitus (NIDDM) pati ents. To examine the direct effect of troglitazone on glucose metaboli sm and insulin action in skeletal muscle, we infused troglitazone solu tion into perfused rat hindlimbs in the presence of 6 mmol/L glucose a nd in the absence or presence of insulin, In the absence of insulin. e ven 50 mu mol/L troglitazone did not elicit glucose uptake. Troglitazo ne did increase lactate and pyruvate release at concentrations of 20 m u mol/L and higher; however, it decreased the ratio of lactate to pyru vate (L/P ratio) and increased oxygen consumption at concentrations hi gher than 5 and 20 mu mol/L respectively, In hindlimb muscle, 20 mu mo l/L troglitazone decreased glycogen content without changing fructose 2,6-bisphosphate (F2,6P2) content in the absence of insulin. Insulin i nfusion with 250 mu U/mL obtained half-maximal effects, causing a 2.8- fold increase in glucose uptake and a 1.5-fold increase in lactate and pyruvate release. When 20 mu mol/L troglitazone was infused for 30 mi nutes together with 250 mu U/mL insulin, insulin-induced glucose uptak e significantly increased 30 minutes after troglitazone infusion, and this increase was further augmented after withdrawal of troglitazone. In insulin plus troglitazone infusion at 30 minutes after troglitazone removal, glycogen content in hindlimb muscle was significantly decrea sed compared with that obtained with insulin infusion alone. In summar y, in the absence of insulin, troglitazone does not elicit glucose upt ake, but causes an increase in glycolysis accompanied by a decrease in muscle glycogen content and L/P ratio and an increase in oxygen consu mption. In the presence of insulin, troglitazone increases insulin-ind uced glucose uptake, and this increase is further augmented after trog litazone removal. Addition of troglitazone to insulin infusion decreas ed the glycogen content in hindlimb muscle. This decrease in muscle gl ycogen content may trigger an enhancement of insulin-induced glucose u ptake similar to that observed during muscle contraction or epinephrin e treatment. Copyright (C) 1997 by W.B. Saunders Company.