A Thiazolidinedione Improves In Vivo Insulin Action on Skeletal Muscle Glycogen Synthase in Insulin-Resistant Monkeys |
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Authors: | Heidi K Ortmeyer Noni L Bodkin Joseph Haney Shinji Yoshioka Hiroyoshi Horikoshi Barbara C Hansen |
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Institution: | 1. Obesity and Diabetes Research Center, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.;2. Sankyo Company Ltd., Tokyo, Japan, |
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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. |
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