AN ANTIDIABETIC THIAZOLIDINEDIONE POTENTIATES INSULIN STIMULATION OF GLYCOGEN-SYNTHASE IN RAT ADIPOSE-TISSUE

Thiazolidinedione derivatives are a novel class of insulin-sensitizing agents that have demonstrated effective antidiabetic activity in vivo . Here, the effects of the potent thiazolidinedione derivative, AD-507 5, on the rate-limiting enzyme of glycogen synthesis, glycogen synthas e, were investigated in cultured rat adipose tissue. Shortterm preincu bation of adipose tissue with AD-5075 potentiated acute insulin stimul ation of I-form glycogen synthase activity in a concentration-dependen t (EC(50)similar to 61 nM) and time-dependent (t(1/2)similar to 2.3 h) manner. The thiazolidinedione derivative increased the responsiveness of I-form glycogen synthase activity to insulin stimulation at both m aximal and submaximal insulin concentrations. In contrast, it had no e ffect on total glycogen synthase activity. Isoproterenol inhibited acu te insulin activation of I-form glycogen synthase activity in a dose-d ependent manner; maximal inhibition was attained at a concentration of 3 nM. AD-5075 antagonized isoproterenol inhibition of insulin's actio n. The concentration of glycogenolytic agent required to attain maxima l inhibition was increased an order of magnitude in tissue treated wit h the antidiabetic agent. Short term preincubation of adipose tissue u nder hyperglycemic conditions (15 or 25 mM glucose) decreased insulin- stimulated I-form glycogen synthase activity. Concurrent treatment of the tissue with AD-5075 abrogated this glucose toxicity-induced inhibi tion of insulin action. Wortmannin, an inhibitor of phosphatidylinosit ol 3-kinase, blocked insulin activation of glycogen synthase in a dose -dependent manner. Half-maximal inhibition was observed at similar to 0.3 mu M, and maximal inhibition occurred at 1.0 mu M. AD-5075 did not antagonize wortmannin's inhibitory action. These results indicate tha t thiazolidinediones can act directly on adipose tissue to augment an important metabolic effect of insulin and counteract the inhibitory ef fects of catecholamines or hyperglycemia. As insulin stimulation of gl ycogen synthase remains wortmannin inhibitable in the presence of AD-5 075, the effects of thiazolidinediones on insulin signal transduction may be phosphatidylinositol 3-kinase-dependent.