A thiazolidinedione improves in vivo insulin action on skeletal muscle glycogen synthase in insulin-resistant monkeys.

Heidi K Ortmeyer,Noni L Bodkin,Joseph Haney,Barbara C Hansen,Hiroyoshi Horikoshi,Shinji Yoshioka

doi:10.1155/edr.2000.195

Abstract

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.

Highlights

Insulin activation of skeletal muscle glycogen synthase, the rate-limiting enzyme in glycogenesis, is strongly related to insulin-mediated glucose disposal rate in humans and in rhesus monkeys. 3" 16] Insulinmediated skeletal muscle glycogen synthase activity has been shown to be reduced in insulin-resistant states. [3"161 several studies have examined the effects of thiazolidinediones on glycogen synthase activity in vitro,[1"5"2] the effect of thiazolidinediones on in vivo insulin action on skeletal muscle glycogen synthase has not been previously reported
Two normoglycemic insulin-resistant monkeys (R-8 and S-8) showed major declines in plasma insulin levels, in accord with their position at an earlier phase in the progression toward diabetes; they showed improved beta-cell function, these two monkeys showed no measurable improvement in insulin sensitivity, at least as assessed by the euglycemic hyperinsulinemic clamp
Insulin activation of skeletal muscle glycogen synthase by dephosphorylation is a good measure of insulin sensitivity

Summary

Introduction

During a euglycemic hyperinsulinemic clamp the skeletal muscle is the primary site for glucose disposal, and glycogen storage is the primary pathway of this glucose disposal. Insulin activation of skeletal muscle glycogen synthase, the rate-limiting enzyme in glycogenesis, is strongly related to insulin-mediated glucose disposal rate in humans and in rhesus monkeys. 3" 16] Insulinmediated skeletal muscle glycogen synthase activity has been shown to be reduced in insulin-resistant states. [3"161 several studies have examined the effects of thiazolidinediones on glycogen synthase activity in vitro,[1"5"2] the effect of thiazolidinediones on in vivo insulin action on skeletal muscle glycogen synthase has not been previously reported. The purpose of the present study was to determine whether a thiazolidinedione could improve in vivo insulin action during a euglycemic hyperinsulinemic clamp by promoting an increase in skeletal muscle glycogen synthase activity in insulin-resistant monkeys Insulin activation of skeletal muscle glycogen synthase, the rate-limiting enzyme in glycogenesis, is strongly related to insulin-mediated glucose disposal rate in humans and in rhesus monkeys. 3" 16] Insulinmediated skeletal muscle glycogen synthase activity has been shown to be reduced in insulin-resistant states. [3"161 several studies have examined the effects of thiazolidinediones on glycogen synthase activity in vitro,[1"5"2] the effect of thiazolidinediones on in vivo insulin action on skeletal muscle glycogen synthase has not been previously reported.

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