Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity.

Abstract

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,gU/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 < 0.0001; r = 0.68, P < 0.0001) and high (r = 0.75, P < 0.0001; r = 0.74, P < 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 < 0.005; r = 0.41, P < 0.05) and high (r = 0.47, P < 0.05; r = 0.43, P < 0.05) plasma insulin concentrations. In addition, fasting glycogen synthase phosphatase activity was correlated with glycogen synthase activity after low-(r = 0.47, P < 0.05) and high-(r = 0.50, P < 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.

Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus.

“…When a defect in insulin's ability to activate glycogen synthase has been reported previously, it has usually been accompanied by a corresponding reduced rate of glucose uptake into insulin-sensitive tissues (e.g., 7,[12][13][14][15][16]. This association has lead to the suggestion that a causal relationship exists between insulin-stimulation ofglycogen synthase and glucose uptake (7,13,14).…”

“…Although impaired muscle glycogen synthase activity in response to insulin has been well documented in a number of insulin-resistant states (7,(12)(13)(14)(15)(16)(17), little is known about the nature or extent of these defects. In a previous study carried out during steadystate glucose clamp conditions and insulin levels of 300 pmol/ liter, we documented that muscle glycogen synthase activity (expressed as fractional velocity) was reduced by 40% in NIDDM but could be normalized by increasing insulin levels fourfold ( 17).…”

“…In animals, diabetes induced by streptozotocin, alloxan, or pancreatectomy has been shown to blunt the ability of insulin to promote glucose incorporation into glycogen (8,9) as well as the ability ofinsulin to lower the sensitivity of the enzyme for G6P (10, 1 1). A number of recent studies conducted in human subjects have also documented reduced glycogen synthase activity in insulinresistant states including NIDDM (7,(12)(13)(14)(15)(16)(17). However, the nature and extent ofthe glycogen synthase defect in muscle and its role in reduced glycogen formation in NIDDM has not yet been clearly elucidated.…”

“…However, the nature and extent ofthe glycogen synthase defect in muscle and its role in reduced glycogen formation in NIDDM has not yet been clearly elucidated. Bogardus and co-workers have reported correlations between muscle glycogen synthase activity and insulin-mediated glucose uptake in subjects with varying insulin sensitivity, implying that glycogen synthase activity is impaired in NIDDM, although the defects were not quantitated at rates of tissue glucose uptake comparable to normal subjects (7,12,13). In subjects with frank NIDDM, Wright et al calculated muscle glycogen synthase activity to be 25% less than control subjects after ingesting a meal (14).…”

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

“…However, it should be emphasized that, even if the defect in hexokinase II were corrected, a severe defect in glucose transport most likely would remain (11) and become rate limiting. It also should be pointed out that the observed defect in in vivo muscle glucose phosphorylation observed in the present study could result from a defect distal to hexokinase, i.e., glycogen synthase (15,26,32,48,59,62) or glycolysis/ glucose oxidation (1,22,59), with an increase in glucose 6-phosphate levels (37,40,42,63,64) and product inhibition of hexokinase. Consistent with this scenario, pervious studies have indicated a rate-limiting step for glucose metabolism beyond glucose phosphorylation/glucose 6-phosphate (46,51), and elevated muscle glucose 6-phopshate concentrations have been demonstrated in insulin-resistant rhesus monkeys during insulin infusion (46).…”