Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity.
Insulin-mediated glycogen synthase activity in skeletal muscle correlates with the rate of insulin-mediated glycogen deposition and is reduced in human subjects with insulin resistance. To assess the role of glycogen synthase phosphatase as a possible mediator of reduced glycogen synthase activity, we studied 30 Southwestern American Indians with a broad range of insulin action in vivo. Percutaneous biopsies of the vastus lateralis muscle were performed before and during a 440-min euglycemic clamp at plasma insulin concentrations of 89 +/- 5 and 1,470 +/- 49 microU/ml (mean +/- SEM); simultaneous glucose oxidation was determined by indirect calorimetry. After insulin stimulation, glycogen synthase activity was correlated with the total and nonoxidative glucose disposal at both low (r = 0.73, P less than 0.0001; r = 0.68, P less than 0.0001) and high (r = 0.75, P less than 0.0001; r = 0.74, P less than 0.0001) plasma insulin concentrations. Fasting muscle glycogen synthase phosphatase activity was correlated with both total and nonoxidative glucose disposal rates at the low (r = 0.48, P less than 0.005; r = 0.41, P less than 0.05) and high (r = 0.47, P less than 0.05; r = 0.43, P less than 0.05) plasma insulin concentrations. In addition, fasting glycogen synthase phosphatase activity was correlated with glycogen synthase activity after low- (r = 0.47, P less than 0.05) and high- (r = 0.50, P less than 0.01) dose insulin stimulations. These data suggest that the decreased insulin-stimulated glucose disposal and reduced glycogen synthase activation observed in insulin resistance could be secondary to a low fasting glycogen synthase phosphatase activity.
Freymond
D
D
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona 85016.
Bogardus
C
C
Okubo
M
M
Stone
K
K
Mott
D
D
D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology; D004789:Enzyme Activation; D005215:Fasting; D005260:Female; D006006:Glycogen Synthase / Q000378:metabolism*; D006007:Glycogen-Synthase-D Phosphatase / Q000378:metabolism*; D006801:Humans; D007198:Indians, North American; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009132:Muscles / Q000201:enzymology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
D007328:Insulin; D006006:Glycogen Synthase; D010749:Phosphoprotein Phosphatases; D006007:Glycogen-Synthase-D Phosphatase