R-102380

Thiazolidinediones (TZD) have been shown to have anti‐diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin‐mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R‐102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate‐limiting enzyme in glycogen synthesis, 4 insulin‐resistant obese monkeys were given I mg/kg/ day R‐102380 p.o. for a 6‐week period. Skeletal muscle GS activity and glucose 6‐phosphate (G6P) content were compared between pre‐dosing and dosing periods before and during the maximal insulin‐stimulation of a euglycemic hyperinsulinemic clamp.Compared to pre‐dosing, insulin‐stimulated GS activity and G6P content were increased by this TZD: GS independent activity (p = 0.02), GS total activity (p = 0.005), GS fractional activity (p = 0.06) and G6P content (p = 0.02). The change in GS activity induced by in vivo insulin (insulin‐stimulated minus basal) was also increased by this TZD: GS independent activity (p = 0.03) and GS fractional activity (p = 0.04).We conclude that the TZD R‐102380 improves insulin action at the skeletal muscle in part by increasing the activity of glycogen synthase. This improvement in insulin sensitivity may be a key factor in the anti‐diabetic effect of the thiazolidinedione class of agents.