Submitted on October 6, 2004
Accepted on March 2, 2005
Skeletal muscle glycogen synthase subcellular localization: effects of insulin and PPAR-
agonist (K-111) administration in rhesus monkeys
Heidi K Ortmeyer1*, Yohannes Adall2, Karina R Marciani2, Andreas Katsiaras3, Alice S Ryan3, Noni L Bodkin2, and Barbara C Hansen2
1 Obesity and Diabetes Research Center, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA; Geriatric Research, Education and Clinical Center, Baltimore VA Health Care Center, Department of Medicine, University of Maryland, Baltimore, MD, USA
2 Obesity and Diabetes Research Center, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA
3 Geriatric Research, Education and Clinical Center, Baltimore VA Health Care Center, Department of Medicine, University of Maryland, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: hortmeye{at}umaryland.edu.
Insulin covalently and allosterically regulates glycogen synthase (GS) and may also cause the translocation of GS from glycogen-poor to glycogen-rich locations. We examined the possible role of subcellular localization of GS and glycogen in insulin activation of GS in skeletal muscle of six obese monkeys, and determined whether a) insulin stimulation during a hyperinsulinemic euglycemic clamp and/or PPAR-
agonist treatment (K-111, 3 mg/kg/day, Kowa Co.,Ltd.) induced translocation of GS and b) translocation of GS was associated with insulin activation of GS. GS and glycogen were present in all fractions obtained by differential centrifugation, except for the cytosolic fraction, under both basal and insulin-stimulated conditions. We found no evidence for translocation of GS by insulin. GS total (GST) activity was strongly associated with glycogen content (r=0.70, p<0.001). Six weeks of treatment with K-111 increased GST activity in all fractions, except the cytosolic fraction, and mean GST activity, GS independent activity and glycogen content were significantly higher in the insulin-stimulated samples compared to basal samples, effects not seen with vehicle. The increase in GST activity was strongly related to the increase in glycogen content during the hyperinsulinemic euglycemic clamp after K-111 administration (r=0.74, p<0.001). Neither GS protein expression nor GS gene expression were affected by insulin or by K-111 treatment. We conclude that (1) in vivo insulin does not cause translocation of GS from a glycogen-poor to a glycogen-rich location in primate skeletal muscle and (2) the mechanism of action of K-111 to improve insulin sensitivity includes an increase in GST activity without an increase in GS gene or protein expression.
