PIOGLITAZONE TREATMENT FOR 7 DAYS FAILED TO CORRECT THE DEFECT IN GLUCOSE-TRANSPORT AND GLUCOSE-TRANSPORTER TRANSLOCATION IN OBESE ZUCKER RAT (FA FA) SKELETAL-MUSCLE PLASMA-MEMBRANES/

Insulin resistance in the obese (fa/fa) Zucker rat is associated with decreased insulin stimulated glucose transport in skeletal muscle, due primarily to a failure of insulin to stimulate GLUT4 translocation to the plasma membrane from an intracellular pool (1). The thiazolidined ione analog Pioglitazone (PIO) has been shown to improve glucose toler ance in this and other animal models of insulin resistance. The curren t study was designed to determine whether 7 days of Pioglitazone treat ment (20 mg/kg/day by gavage) would improve glucose transport and/or g lucose transporter translocation and intrinsic activity in plasma memb ranes prepared from hindlimb skeletal muscle of obese Zucker (fa/fa) r ats. Basal plasma glucose and insulin concentrations in these animals were unchanged by Pioglitazone, while basal plasma triglyceride and no nesterified fatty acid concentrations (NEFA) were reduced by Pioglitaz one treatment (501+/-88 vs 161+/-1 3 mg/dl, P<0.0001) and (678+/-95 vs 467+/-75 mu M, P<0.05) respectively. Pioglitazone had no effect on ba sal or insulin stimulated glucose influx (V-max or K-m) into plasma me mbrane vesicles determined under equilibrium exchange conditions compa red to controls. Plasma membrane glucose transporter number (R(o)) (me asured by cytochalasin B binding) under basal or insulin stimulated co nditions was unchange by Pioglitazone and R(o) failed to increase foll owing insulin stimulation in either group. Glucose transporter turnove r number (V-max/R(o)) increased 2-fold with insulin stimulation compar ed to basal in both control and Pioglitazone groups, similar to turnov er numbers observed in normal rats. These data confirm that impaired g lucose transporter translocation in muscle of the Zucker rat is a majo r factor contributing to its insulin resistance. We conclude that the improved glucose tolerance observed in fa/fa rats following Pioglitazo ne treatment is not due to an improvement in basal or insulin stimulat ed skeletal muscle plasma membrane glucose transport or glucose transp orter translocation and that Pioglitazone treatment does not affect tr ansporter intrinsic activity. (C) 1995 Academic Press, Inc.